TWI802635B - Substituted pyrrolo[2,3-d]pyrimidines compounds as ret kinase inhibitors - Google Patents

Abstract

Provided herein are compounds of the Formula I:

and tautomers, stereoisomers and pharmaceutically acceptable salts and solvates thereof, wherein R¹ , R² and R^y have the meanings given in the specification, which are inhibitors of RET kinase and are useful in the treatment and prevention of diseases which can be treated with a RET kinase inhibitor, including RET-associated diseases and disorders.

Description

Substituted pyrrolo[2,3-D]pyrimidine compounds as RET kinase inhibitors

The present invention relates to novel compounds exhibiting inhibition of rearranged transfection (RET) kinases, pharmaceutical compositions comprising the compounds, methods of preparing the compounds, and the use of the compounds in therapy. More particularly, it relates to substituted pyrrolo[2,3-d]pyrimidine compounds that are useful in the treatment and prevention of diseases that are treatable with RET kinase inhibitors, including RET-associated diseases and disorders.

RET is a single transmembrane receptor belonging to the tyrosine kinase superfamily that is required for the normal development, maturation and maintenance of several tissues and cell types (Mulligan, LM, Nature Reviews Cancer , 2014, 14, 173-186 ). The extracellular portion of RET kinase contains four calcium-dependent cadherin-like repeats involved in ligand binding and a proximal membrane cysteine-rich region required for proper folding of the extracellular domain of RET, while the cytoplasmic Partly includes two tyrosine kinase subdomains.

RET signaling is mediated by the binding of a group of soluble proteins of the glial cell line-derived neurotrophic factor (GDNF) family ligand (GFL), which also includes neurturin (NTRN), Artesunate (artemin; ARTN) and persephin (PSPN) (Arighi et al., Cytokine Growth Factor Rev. , 2005, 16, 441-67). Unlike other receptor tyrosine kinases, RET does not bind directly to GFL and requires another co-receptor: that is, one of the four GDNF family receptor-α (GFRα) family members, which act by glycosylated phospholipids Inositol bonds tether to the cell surface. GFL forms binary complexes with members of the GFRα family, which in turn bind to RET and recruit it to cholesterol-rich membrane subdomains called lipid rafts, where RET signaling occurs.

Following ligand-co-receptor complex binding, RET dimerization and autophosphorylation on intracellular tyrosine residues recruits adapters and signaling proteins to stimulate multiple downstream pathways. Binding of attachment proteins to these docking sites results in the activation of Ras-MAPK and PI3K-Akt/mTOR signaling pathways, or in the recruitment of the CBL family of ubiquitin ligases that are involved in the RET-mediated function of RET function in downregulation.

Aberrant RET expression and/or activity has been demonstrated in various cancers and gastrointestinal disorders, such as irritable bowel syndrome (IBS).

Substituted pyrrolo[2,3-d]pyrimidine compounds have now been found to be inhibitors of RET kinase and are useful in the treatment of diseases, such as proliferative diseases, such as cancer.

Accordingly, provided herein are compounds of formula I:

and tautomers, stereoisomers and pharmaceutically acceptable salts and solvates thereof, wherein R ¹ , R ² and R ^y are as defined herein.

Also provided herein is a pharmaceutical composition comprising a mixture of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable diluent or carrier.

Also provided herein is a method for inhibiting cell proliferation in vitro or in vivo, the method comprising allowing cells to be treated with an effective amount of a compound of formula I as defined herein or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition thereof touch.

Also provided herein is a method of treating a RET-associated disease or disorder in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound of formula I as defined herein, or a pharmaceutically acceptable salt thereof Or a solvate or a pharmaceutical composition thereof.

Also provided herein is a method of treating cancer and/or inhibiting metastasis associated with a particular cancer in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound of formula I as defined herein or a medicament thereof Pharmaceutically acceptable salts or solvates or pharmaceutical compositions thereof.

Also provided herein is a method of treating irritable bowel syndrome (IBS) and/or pain associated with IBS in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound of formula I as defined herein or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof.

Also provided is a method of providing supportive care to a cancer patient, including preventing or minimizing gastrointestinal disorders, such as diarrhea, associated with treatment (including chemotherapeutic treatment), the method comprising administering to the patient a therapeutically effective amount of The defined compound of formula I or its pharmaceutically acceptable salt or solvate or its pharmaceutical composition.

Also provided herein is a compound of formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, for use in therapy.

Also provided herein is a compound of formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, for use in the treatment of cancer and/or the inhibition of metastasis associated with a particular cancer.

Also provided herein is a compound of formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, for use in the treatment of irritable bowel syndrome (IBS) or pain associated with IBS.

Also provided is a compound of formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof for use in providing supportive care to cancer patients, including prophylaxis or minimization and treatment (including chemotherapy) Sexual therapy) related gastrointestinal disorders, such as diarrhea.

Also provided herein is a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, for use in inhibiting RET kinase activity.

Also provided herein is a compound of formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, for use in the treatment of a RET-associated disease or disorder.

Also provided herein is the use of a compound of formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for treating cancer and/or inhibiting metastasis associated with a particular cancer.

Also provided herein is the use of a compound of formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of irritable bowel syndrome (IBS) or pain associated with IBS.

Also provided herein is the use of a compound of formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for providing supportive care to cancer patients, including the prevention or minimization of Treatment, including chemotherapeutic treatment, of associated gastrointestinal disorders, such as diarrhea.

Also provided herein is the use of a compound of formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for inhibiting RET kinase activity.

Also provided herein is the use of a compound of formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of a RET-associated disease or disorder.

Also provided herein are methods for treating cancer in a patient in need thereof, the method comprising (a) determining whether the cancer is associated with RET gene, RET kinase, or dysregulation of the expression or activity or level of either (e.g. RET-associated cancer); and (b) administering to the patient a therapeutically effective amount of a compound of Formula I if the cancer is determined to be associated with a disorder in the expression or activity or level of the RET gene, RET kinase, or either (e.g. RET-associated cancer) or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof.

Also provided herein are pharmaceutical combinations comprising (a) a compound of formula I or a pharmaceutical composition thereof for use in the treatment of cancer (e.g., RET-associated cancers, such as RET-associated cancers having one or more RET inhibitor resistance mutations) in a patient in need thereof A pharmaceutically acceptable salt or solvate, (b) other therapeutic agent, and (c) at least one pharmaceutically acceptable carrier selected as the case may be, wherein the compound of formula I or its pharmaceutically acceptable salt Or solvates and other therapeutic agents are formulated for simultaneous, separate or sequential use in separate compositions or doses for the treatment of cancer, wherein the compound of formula I or its pharmaceutically acceptable salt or solvate and other therapeutic Dosage amounts are collectively effective in treating cancer. Also provided herein are pharmaceutical compositions comprising such combinations. Also provided herein is the use of such combinations in the manufacture of a medicament for the treatment of cancer. Also provided herein are commercially available packages or products comprising such combinations as combined preparations for simultaneous, separate or sequential use; and methods of treating cancer in a patient in need thereof.

Also provided herein is a method for reversing or preventing acquired resistance to anticancer drugs, which comprises administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof to a patient, the patient having the ability to develop anticancer drugs Risk of acquired resistance to anticancer drugs or have acquired resistance to anticancer drugs. In some embodiments, a dose of the anticancer drug is administered to the patient (eg, substantially at the same time as the dose of the compound of formula I or a pharmaceutically acceptable salt or solvate thereof is administered to the patient) .

Also provided herein is a method of delaying and/or preventing the emergence of cancer resistant to anticancer drugs in an individual, comprising administering to the individual an effective amount of the formula I A compound or a pharmaceutically acceptable salt or solvate thereof.

Also provided herein is a method of treating an individual with cancer that has an increased likelihood of developing resistance to an anticancer drug, the method comprising administering to the individual before, during, or after administering (b) an effective amount of an anticancer drug Administering (a) an effective amount of a compound of formula I.

Also provided is a method of treating an individual with a RET-associated cancer having one or more RET inhibitor resistance mutations that increase the cancer's resistance to a first RET inhibitor (such as one or more of the following amine groups Acid substitutions: kinase domain (e.g. amino acid position 700 to 1012 in wild-type RET protein), gatekeeper amino acid (e.g. amino acid position 804 in wild-type RET protein), P-loop (e.g. amino acid positions 730-737 in ), X-DFG residues (such as amino acid position 891 in wild-type RET protein), ATP cleft solvent leading edge amino acids (such as amino acid in wild-type RET protein positions 806-811), the activation loop (such as amino acid positions 891-916 in the wild-type RET protein), the C-helix and the loop before the C-helix (such as amino acid positions 768-788 in the wild-type RET protein ) and/or ATP binding sites (such as amino acid positions 730-733, 738, 756, 758, 804, 805, 807, 811, 881 and 892 in wild-type RET protein) (such as amino acid position 804 substitutions such as V804M, V804L or V804E, or substitutions at amino acid position 810 such as G810S, G810R, G810C, G810A, G810V and G810D), and/or one or more of the RET inhibitors listed in Tables 3 and 4 resistance mutation), the method comprises administering a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, before, during or after administration of another anticancer drug (eg, a second RET kinase inhibitor). See also J. Kooistra, GK Kanev, OPJ Van Linden, R. Leurs, IJP De Esch and C. De Graaf, "KLIFS: A structural kinase-ligand interaction database," Nucleic Acids Res. , Vol. 44, No. D1 , pp. D365-D371, 2016; and OPJ Van Linden, AJ Kooistra, R. Leurs, IJP De Esch and C. De Graaf, "KLIFS: A knowledge-based structural database to navigate kinase-ligand interaction space," J. Med. Chem. , Vol. 57, No. 2, pp. 249-277, 2014, which is incorporated herein by reference in its entirety. In some embodiments, the wild-type RET protein is an exemplary wild-type RET protein described herein.

Also provided is a method of treating an individual with a RET-associated cancer comprising administering a compound of formula I or Its pharmaceutically acceptable salt or solvate.

Also provided herein is a method of treating irritable bowel syndrome (IBS) in a patient in need thereof, the method comprising (a) determining whether IBS is associated with a dysregulation of the expression or activity or level of the RET gene, RET kinase, or either; and (b) administering to the patient a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof or Solvates or pharmaceutical compositions thereof.

Also provided herein is a pharmaceutical combination for treating irritable bowel syndrome (IBS) in a patient in need thereof, comprising administering (a) a compound of general formula I or a pharmaceutically acceptable salt or solvate thereof, ( b) other therapeutic agents, and (c) at least one pharmaceutically acceptable carrier selected as the case may be, to be used simultaneously, separately or sequentially for the treatment of IBS, wherein the compound of formula I or its pharmaceutically acceptable salt Or the amount of the solvate and the other therapeutic agent are jointly effective in treating IBS. Also provided herein are pharmaceutical compositions comprising such combinations. Also provided herein is the use of such combinations in the manufacture of a medicament for the treatment of IBS. Also provided herein are commercially available packages or products comprising such combinations as combined preparations for simultaneous, separate or sequential use; and methods of treating IBS in a patient in need thereof.

Also provided herein is a method of preparing a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof.

Also provided herein is a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, obtained by a process for the preparation of the compound as defined herein.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials are described herein for use in the present invention; other suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

Other features and advantages of the present invention will be apparent from the following detailed description and drawings, as well as the claims.

Cross References to Related Applications

This application claims priority over U.S. Application Nos. 62/676,484, filed May 25, 2018, 62/669,298, filed May 9, 2018, and 62/619,060, filed January 18, 2018 rights, each of which is incorporated herein by reference in its entirety.

Provided herein are compounds of formula I:

And its tautomers, stereoisomers and pharmaceutically acceptable salts and solvates, among which:

R ^is a 5-membered heteroaryl ring having 2-3 ring heteroatoms independently selected from N, O, and S, wherein ^R is optionally substituted with 1-3 substituents independently selected from halogen , C1-C6 alkyl, fluoro C1-C6 alkyl, hydroxy C1-C6 alkyl, dihydroxy C2-C6 alkyl-, (C1-C6 alkoxy) C1-C6 alkyl-, C2-C6 alkenyl , Cyc ¹ , hetCyc ¹ , Ar ¹ , hetAr ¹ , (C1-C6 alkyl)C(=O)-, (C1-C6 alkyl) ₂ -P(=O)- and R'R''NC( =O)-, wherein R' is hydrogen and R'' is hydrogen, C1-C6 alkyl or ^Cyc2 ;

Cyc ¹ is a 3-6 membered saturated or partially unsaturated cycloalkyl ring, which is optionally substituted by one or more substituents independently selected from hydroxyl, C1-C6 alkyl and pendant oxy;

hetCyc ¹ is a 4-6 membered saturated or partially unsaturated heterocyclic ring, which has 1-2 ring heteroatoms independently selected from N and O and optionally selected from one or more rings independently selected from C1-C6 alkyl, Substituents for hydroxyl and pendant oxygen groups;

^Ar is phenyl optionally substituted by one or more substituents independently selected from C1-C6 alkyl, fluoroC1-C6 alkyl, halogen and hydroxyl;

Cyc ² is a C3-C6 cycloalkyl group optionally substituted by a hydroxyl group;

hetAr ¹ is a 5-6 membered heteroaryl ring having 1-3 ring nitrogen atoms and optionally one or more independently selected from C1-C6 alkyl, fluorine C1-C6 alkyl, halogen, hydroxyl and Benzyl substituent substitution;

R ² is hydrogen, C1-C6 alkyl, fluoro C1-C6 alkyl, cyano C1-C6 alkyl, hydroxy C1-C6 alkyl, Ar ² , (Ar ² ) C1-C6 alkyl-, hetCyc ² , Cyc ³ or (Cyc ³ ) C1-C6 alkyl-;

Ar ² is phenyl, which is optionally substituted by one or more substituents independently selected from the following: C1-C6 alkyl, fluoroC1-C6 alkyl, halogen and hydroxyl;

Cyc ³ is C3-C6 cycloalkyl, which is optionally substituted by hydroxyC1-C6 alkyl;

hetCyc ² is a 4-6 membered saturated heterocycle having 1-2 ring heteroatoms independently selected from N and O; and

R ^y is hydrogen, HC(=O)-, hydroxy C1-C6 alkyl-, C1-C6 alkyl or amino C1-C6 alkyl-.

In some embodiments, the present invention provides compounds of formula I:

And its tautomers, stereoisomers and pharmaceutically acceptable salts and solvates, among which:

R ^is a 5-membered heteroaryl ring having 2-3 ring heteroatoms independently selected from N, O, and S, wherein ^R is optionally substituted with 1-3 substituents independently selected from halogen , C1-C6 alkyl, fluoro C1-C6 alkyl, hydroxy C1-C6 alkyl, (C1-C6 alkoxy) C1-C6 alkyl-, C2-C6 alkenyl, Cyc ¹ , hetCyc ¹ , Ar ¹ , hetAr ¹ , (C1-C6 alkyl) C(=O)-, (C1-C6 alkyl) ₂ -P(=O)- and R'R''NC(=O)-, where R' is Hydrogen and R'' is hydrogen, C1-C6 alkyl or Cyc ² ;

Cyc ¹ is a 3-6 membered saturated or partially unsaturated cycloalkyl ring, which is optionally substituted by one or more substituents independently selected from hydroxyl, C1-C6 alkyl and pendant oxy;

hetCyc ¹ is a 4-6 membered saturated or partially unsaturated heterocyclic ring, which has 1-2 ring heteroatoms independently selected from N and O and optionally selected from one or more rings independently selected from C1-C6 alkyl, Substituents for hydroxyl and pendant oxygen groups;

^Ar is phenyl optionally substituted by one or more substituents independently selected from C1-C6 alkyl, fluoroC1-C6 alkyl, halogen and hydroxyl;

Cyc ² is a C3-C6 cycloalkyl group optionally substituted by a hydroxyl group;

hetAr ¹ is a 5-6 membered heteroaryl ring having 1-3 ring nitrogen atoms and optionally one or more independently selected from C1-C6 alkyl, fluorine C1-C6 alkyl, halogen, hydroxyl and Benzyl substituent substitution;

R ² is hydrogen, C1-C6 alkyl, fluoro C1-C6 alkyl, cyano C1-C6 alkyl-, hydroxyl C1-C6 alkyl, C3-C6 cycloalkyl or (C3-C6 cycloalkyl) C1 -C6 alkyl-; and

R ^y is hydrogen, HC(=O)- or hydroxy C1-C6 alkyl-.

For complex chemical names used herein, a substituent is usually named before the group to which it is attached. For example, methoxyethyl comprises an ethyl backbone with methoxy substituents.

The term "halogen" means -F (sometimes referred to herein as "fluoro" or "fluoros"), -Cl, -Br, and -I.

As used herein, the term "C1-C6 alkyl" refers to a saturated linear or branched monovalent hydrocarbon group having one to six carbon atoms. Examples include (but are not limited to) methyl, ethyl, 1-propyl, isopropyl, 1-butyl, isobutyl, second-butyl, third-butyl, 2-methyl-2-propyl , pentyl, neopentyl and hexyl.

As used herein, the term "fluoro C1-C6 alkyl" refers to a C1-C6 alkyl group as defined herein wherein one to three hydrogen atoms are respectively replaced by one to three fluorine atoms. Examples include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, and 2,2,2-trifluoroethyl.

As used herein, the term "C2-C6 alkenyl" refers to a straight or branched monounsaturated hydrocarbon chain having two to six carbon atoms. Examples include, but are not limited to, vinyl, propenyl, butenyl, or pentenyl.

As used herein, the term "C1-C6 alkoxy" refers to a saturated linear or branched monovalent alkoxy group having one to six carbon atoms, wherein the group is on an oxygen atom. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy and tert-butoxy.

As used herein, the term "(C1-C6 alkoxy)C1-C6 alkyl" refers to a saturated linear or branched monovalent group having one to six carbon atoms, one of which is defined as herein C1-C6 alkoxy substitution. _{Examples include} methoxymethyl ( _CH3OCH2- ) and _methoxyethyl ( _CH3OCH2CH2- ).

As used herein, the term "hydroxy C1-C6 alkyl" refers to a saturated linear or branched monovalent alkyl group having one to six or two to six carbon atoms, respectively, in which one carbon atom is substituted by a hydroxyl group.

As used herein, the term "dihydroxy C2-C6 alkyl" refers to a saturated linear or branched monovalent alkyl group having two to six carbon atoms, respectively, in which two carbon atoms are each substituted by a hydroxyl group.

As used herein, the term "cyano-C1-C6 alkyl" refers to a saturated linear or branched chain monovalent alkane having one to six or two to six carbon atoms, respectively, in which one carbon atom is substituted by a cyano group. base.

As used herein, the term "amino C1-C6 alkyl" refers to a saturated linear chain having one to six or two to six carbon atoms in which one carbon atom is substituted by an amino group (ie, NH ₂ ), respectively. Or a branched chain monovalent alkyl group.

As used herein, the term "C3-C6 cycloalkyl" refers to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

As used herein, the term "(C3-C6 cycloalkyl)C1-C3 alkyl" refers to a C1-C3 alkyl group as defined herein wherein one carbon atom is substituted by a C3-C6 cycloalkyl ring. An example is cyclobutylmethyl.

。As used herein, the term "pendant oxy" means an oxygen double bonded to a carbon atom, ie =O. For example, in one embodiment, when referring to hetCyc ^a , a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O and substituted with a pendant oxo group can be, for example, pendant Oxy-substituted pyrrolidinyl rings (eg, pyrrolidinonyl rings), which can be represented by the following structures:

.

As used herein, the term "compound" is intended to include all stereoisomers, geometric isomers, tautomers and isotopes of the stated structure. Unless otherwise stated, compounds identified herein by name or structure as one particular tautomeric form are intended to include the other tautomeric forms.

。As used herein, the term "tautomer" refers to compounds whose structures differ significantly in the arrangement of atoms, but in which there is easy and rapid equilibration, and it is understood that the compounds presented herein may be depicted as different tautomers isomers, and when compounds have tautomeric forms, all tautomeric forms are intended to be within the scope of the invention, and the naming of compounds does not exclude any tautomers. Examples of tautomeric forms include the following:

.

It is understood that certain compounds provided herein may contain one or more asymmetric centers and thus may be prepared and isolated as a mixture of isomers, such as a racemic mixture, or in enantiomerically pure form.

In one embodiment, R ^is an oxazolyl or isoxazolyl ring optionally substituted with 1-2 substituents independently selected from the group consisting of halogen, C1-C6 alkyl, fluoroC1-C6 alkane group, hydroxy C1-C6 alkyl, dihydroxy C2-C6 alkyl, (C1-C6 alkoxy) C1-C6 alkyl-, C2-C6 alkenyl, Cyc ¹ , hetCyc ¹ , Ar ¹ , hetAr ¹ , (C1-C6 alkyl)C(=O)-, (C1-C6 alkyl) ₂ -P(=O)- and R'R''NC(=O)-, where R' is hydrogen and R'' is hydrogen, C1-C6 alkyl or Cyc ² .

In one embodiment, R ^is an isoxazolyl ring optionally substituted with 1-2 substituents independently selected from the group consisting of halogen, C1-C6 alkyl, fluoroC1-C6 alkyl, hydroxyl C1 -C6 alkyl, dihydroxy C2-C6 alkyl, (C1-C6 alkoxy) C1-C6 alkyl-, C2-C6 alkenyl, Cyc ¹ , hetCyc ¹ , Ar ¹ , hetAr ¹ , (C1-C6 Alkyl) C(=O)-, (C1-C6 alkyl) ₂ -P(=O)- and R'R''NC(=O)-, wherein R' is hydrogen and R'' is hydrogen, C1-C6 alkyl or Cyc ² .

In one embodiment, R ^is an isoxazolyl ring optionally substituted with 1-2 substituents independently selected from the group consisting of halogen, C1-C6 alkyl, fluoroC1-C6 alkyl, hydroxyl C1 -C6 alkyl, dihydroxy C2-C6 alkyl, (C1-C6 alkoxy) C1-C6 alkyl-, C2-C6 alkenyl, Cyc ¹ , hetCyc ¹ , Ar ¹ , hetAr ¹ , (C1-C6 Alkyl) C(=O)-, (C1-C6 alkyl) ₂ -P(=O)- and R'R''NC(=O)-, wherein R' is hydrogen and R'' is hydrogen, C1-C6 alkyl or Cyc ² .

。In one embodiment, ^R is selected from the following structures:

.

In one embodiment, R ¹ is an isoxazolyl ring optionally substituted with 1-2 substituents independently selected from the group consisting of halogen, Cyc ¹ , dihydroxy C2-C6 alkyl, hetAr ¹ and R 'R''NC(=O)-, wherein R' is hydrogen and R'' is hydrogen, C1-C6 alkyl or ^Cyc2 .

In one embodiment, R ¹ is an isoxazolyl ring optionally substituted with 1-2 substituents independently selected from the group consisting of halogen, Cyc ¹ , hetAr ¹ and R'R''NC(=O )-, wherein R' is hydrogen and R'' is hydrogen, C1-C6 alkyl or Cyc ² .

In one embodiment, ^R is

wherein R ^a and R ^b are independently selected from hydrogen, halogen, Cyc ¹ , dihydroxy C2-C6 alkyl, hetAr ¹ and R'R''NC(=O)-, wherein R' is hydrogen and R'' is Hydrogen, C1-C6 alkyl or ^Cyc2 .

In one embodiment, ^R is

其中R^a 及R^b 獨立地選自氫、鹵素、Cyc¹ 、hetAr¹ 及R'R''NC(=O)-，其中R'為氫且R''為氫、C1-C6烷基或Cyc² 。

wherein R ^a and R ^b are independently selected from hydrogen, halogen, Cyc ¹ , hetAr ¹ and R'R''NC(=O)-, wherein R' is hydrogen and R'' is hydrogen, C1-C6 alkyl or Cyc ² .

In one embodiment, R ^a is Cyc ¹ .

In one embodiment, R ^b is selected from hydrogen, halogen, hetAr ¹ and R'R''NC(=O)-, wherein R' is hydrogen and R'' is hydrogen, C1-C6 alkyl or ^Cyc2 .

In one embodiment, ^Rb is hydrogen.

In one embodiment, R ^b is halogen.

In one embodiment, R ^b is hetAr ¹ .

In one embodiment, R ^b is R'R''NC(=0)-, wherein R' is hydrogen and R'' is hydrogen, C1-C6 alkyl, or ^Cyc2 .

In one embodiment, R ^b is dihydroxy C2-C6 alkyl. In one embodiment, ^Rb is -CH(OH) _CH2 (OH).

。In one embodiment, ^R is selected from the following structures:

.

。In one embodiment, ^R is selected from the following structures:

.

In one embodiment, R ¹ is a pyrazolyl ring, optionally 1-3 independently selected from C1-C6 alkyl, fluoro C1-C6 alkyl, C2-C6 alkenyl, Cyc ¹ , hetCyc ¹ Or the substituent of Ar ¹ is substituted.

In one embodiment, R ^is a pyrazolyl ring having the following structure:

in

R ^c is hydrogen, C1-C6 alkyl, fluoro C1-C6 alkyl, C2-C6 alkenyl, Cyc ¹ , hetCyc ¹ or Ar ¹ ;

R ^d is hydrogen, C1-C6 alkyl, ^Cyc1 or ^hetCyc1 ; and

R ^e is hydrogen or C1-C6 alkyl.

In one embodiment, R ^is a pyrazolyl ring having the following structure:

in

R ^c is hydrogen, C1-C6 alkyl, fluoro C1-C6 alkyl, C2-C6 alkenyl, Cyc ¹ , hetCyc ¹ or Ar ¹ ;

R ^d is C1-C6 alkyl, Cyc ¹ or hetCyc ¹ ; and

R ^e is hydrogen or C1-C6 alkyl.

In one embodiment, R ^c is hydrogen.

In one embodiment, R ^c is C1-C6 alkyl.

In one embodiment, R ^c is fluoro C1-C6 alkyl.

In one embodiment, R ^c is C2-C6 alkenyl.

In one embodiment, R ^c is Cyc ¹ .

In one embodiment, R ^c is hetCyc ¹ .

In one embodiment, R ^c is Ar ¹ .

In one embodiment, ^Rd is hydrogen.

In one embodiment, R ^d is C1-C6 alkyl.

In one embodiment, R ^d is Cyc ¹ .

In one embodiment, R ^d is hetCyc ¹ .

In one embodiment, Re ^is hydrogen.

In one embodiment, R ^e is C1-C6 alkyl.

In one embodiment, R ^is a pyrazolyl ring having the following structure:

in

R ^c is hydrogen, C1-C6 alkyl, fluoro C1-C6 alkyl, C2-C6 alkenyl, Cyc ¹ , hetCyc ¹ or Ar ¹ ;

R ^d is hydrogen, C1-C6 alkyl, ^Cyc1 or ^hetCyc1 ; and

R ^e is hydrogen or C1-C6 alkyl.

。In one embodiment, non-limiting examples of ^R include the following structures:

.

其中R^d 為Cyc¹ 。In one embodiment, R ^is a pyrazolyl ring having the following structure:

wherein R ^d is Cyc ¹ .

In one embodiment, R ^is a triazolyl ring optionally substituted with 1-2 groups independently selected from: halogen, C1-C6 alkyl, fluoroC1-C6 alkyl, hydroxyC1- C6 alkyl, (C1-C6 alkoxy) C1-C6 alkyl-, C2-C6 alkenyl, Cyc ¹ , hetCyc ¹ , Ar ¹ , hetAr ¹ , (C1-C6 alkyl) C(=O)- , (C1-C6 alkyl) ₂ -P(=O)- and R'R''NC(=O)-, wherein R' is hydrogen and R'' is hydrogen, C1-C6 alkyl or Cyc ² .

In one embodiment, R ¹ is a triazolyl ring optionally substituted with a group selected from C 1 -C 6 alkyl and Cyc ¹ .

In one embodiment, ^R is

Wherein R ^f is hydrogen, C1-C6 alkyl or Cyc ¹ .

。In one embodiment, ^R is a triazolyl ring selected from the following structures:

.

In one embodiment, R ¹ is a thiadiazolyl ring optionally substituted with halogen.

。In one embodiment, R ¹ is a halogen substituted thiadiazolyl ring. In one embodiment, ^R is

.

In one embodiment, ^Ry is hydrogen.

In one embodiment, ^Ry is HC(=0)-.

In one embodiment, ^Ry is hydroxyC1-C6alkyl-. In one embodiment, ^Ry is _-CH2OH .

In one embodiment, R ^y is amino C1-C6 alkyl-. In one embodiment, ^Ry _{is -CH2NH2} .

In one embodiment, ^Ry is C1-C6 alkyl. In one embodiment, ^Ry is methyl.

In one embodiment, ^R2 is hydrogen.

。In one embodiment, R ² is (Cyc ³ )C1-C6 alkyl-. In one embodiment, R ² is (C3-C6 cycloalkyl)C1-C6 alkyl-. In one embodiment, ^R is represented by the following structure:

.

In one embodiment, R ² is Cyc ³ , wherein Cyc ³ is C3-C6 cycloalkyl optionally substituted with hydroxy C1-C6 alkyl.

In one embodiment, R ² is C3-C6 cycloalkyl. In one embodiment, R ² is cyclopropyl, cyclopentyl or cyclobutyl.

。In one embodiment, R ² is C3-C6 cycloalkyl substituted with hydroxyC1-C6 alkyl. In one embodiment, ^R is selected from the following structures:

.

In one embodiment, R ² is hetCyc ² , wherein hetCyc ² is a 4-6 membered saturated heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O. In one embodiment, ^R is a 4-6 membered saturated heterocyclic ring with 1 epoxy atom. In one embodiment, R ² is epoxypropylene or tetrahydropyranyl. In one embodiment, R ² is oxetan-3-yl or tetrahydropyran-4-yl.

In one embodiment, R ² is Ar ² , wherein Ar ² is phenyl optionally substituted with one or more substituents independently selected from: C1-C6 alkyl, fluoroC1-C6 alkyl, halogen and hydroxyl. In one embodiment, ^R2 is phenyl.

In one embodiment, R ² is (Ar ² )C1-C6phenyl-. In one embodiment, R ² is (Ar ² )C1-C6 alkyl, wherein Ar ² is phenyl. In one embodiment, R ² is benzyl.

In one embodiment, R ² is hydroxy C1-C6 alkyl. In one embodiment, ^R is represented by the following structure:

。

.

In one embodiment, R ² is cyano C1-C6 alkyl. In one embodiment, ^R is represented by the following structure:

。

.

In one embodiment, R ² is fluoro C1-C6 alkyl. In one embodiment, R ² is 1,1,1-trifluoropropan-2-yl.

In one embodiment, R ² is C1-C6 alkyl. In one embodiment, R ² is isopropyl or tert-butyl.

In one embodiment, compounds of formula I include compounds of formula I-A, wherein:

R ^is a 5-membered heteroaryl ring having 2-3 ring heteroatoms independently selected from N and O, wherein ^R is optionally substituted with 1-2 substituents independently selected from: halogen, C1 -C6 alkyl, Cyc ¹ , dihydroxy C2-C6 alkyl, hetAr ¹ and R'R''NC(=O)-, where R' is hydrogen and R'' is hydrogen, C1-C6 alkyl or Cyc ² ;

Cyc ¹ is a saturated or partially unsaturated cycloalkyl ring with 3-6 members;

Cyc ² is a C3-C6 cycloalkyl group optionally substituted by a hydroxyl group;

hetAr ¹ is a 5-6 membered heteroaryl with 1-2 ring nitrogen atoms;

R ² is hydrogen, C1-C6 alkyl, Ar ² , (Ar ² ) C1-C6 alkyl, hetCyc ² , Cyc ³ or (Cyc ³ ) C1-C6 alkyl-; and

R ^y is hydrogen, HC(=O)-, hydroxy C1-C6 alkyl-, C1-C6 alkyl- or amino C1-C6 alkyl-.

In one embodiment, compounds of formula I include compounds of formula I-A, wherein:

R ^is a 5-membered heteroaryl ring having 2-3 ring heteroatoms independently selected from N and O, wherein ^R is optionally substituted with 1-2 substituents independently selected from: halogen, C1 -C6 alkyl, Cyc ¹ , hetAr ¹ and R'R''NC(=O)-, wherein R' is hydrogen and R'' is hydrogen, C1-C6 alkyl or Cyc ² ;

Cyc ¹ is a saturated or partially unsaturated cycloalkyl ring with 3-6 members;

Cyc ² is a C3-C6 cycloalkyl group optionally substituted by a hydroxyl group;

hetAr ¹ is a 5-6 membered heteroaryl with 1-2 ring nitrogen atoms;

R ² is hydrogen, C1-C6 alkyl or (C3-C6 cycloalkyl) C1-C6 alkyl-; and

R ^y is hydrogen, HC(=O)- or hydroxy C1-C6 alkyl-.

In one embodiment of Formula IA, R ¹ is an isoxazolyl ring optionally substituted with 1-2 substituents independently selected from the group consisting of halogen, Cyc ¹ , dihydroxy C2-C6 alkyl, hetAr ¹ and R'R''NC(=O)-, wherein R' is hydrogen and R'' is hydrogen or C1-C6 alkyl.

In one embodiment of Formula IA, R ¹ is an isoxazolyl ring optionally substituted with 1-2 substituents independently selected from the group consisting of halogen, Cyc ¹ , hetAr ¹ and R'R''NC (=O)-, wherein R' is hydrogen and R'' is hydrogen or C1-C6 alkyl.

In one embodiment of formula IA, ^R is

wherein R ^a and R ^b are independently selected from hydrogen, halogen, Cyc ¹ , dihydroxy C2-C6 alkyl, hetAr ¹ and R'R''NC(=O)-, wherein R' is hydrogen and R'' is Hydrogen, C1-C6 alkyl or ^Cyc2 .

In one embodiment of formula IA, ^R is

wherein R ^a and R ^b are independently selected from hydrogen, halogen, Cyc ¹ , hetAr ¹ and R'R''NC(=O)-, wherein R' is hydrogen and R'' is hydrogen, C1-C6 alkyl or Cyc ² .

In one embodiment of formula IA, R ^a is Cyc ¹ .

In one embodiment of Formula IA, R ^b is selected from hydrogen, halogen, dihydroxy C2-C6 alkyl, hetAr ¹ and R'R''NC(=O)-, wherein R' is hydrogen and R'' is Hydrogen, C1-C6 alkyl or ^Cyc2 .

In one embodiment of formula IA, R ^b is selected from hydrogen, halogen, hetAr ¹ and R'R''NC(=O)-, wherein R' is hydrogen and R'' is hydrogen, C1-C6 alkyl or Cyc ² .

In one embodiment of formula IA, ^Rb is hydrogen.

In one embodiment of Formula IA, R ^b is halogen.

In one embodiment of Formula IA, R ^b is hetAr ¹ .

In one embodiment of Formula IA, R ^b is R'R''NC(=O)-, wherein R' is hydrogen and R'' is hydrogen, C1-C6 alkyl, or ^Cyc2 .

In one embodiment of formula IA, R ^b is dihydroxy C2-C6 alkyl. In one embodiment, ^Rb is -CH(OH) _CH2 (OH).

In one embodiment of formula IA, ^R is

R ^c is hydrogen, C1-C6 alkyl, fluoro C1-C6 alkyl, C2-C6 alkenyl, Cyc ¹ , hetCyc ¹ or Ar ¹ ;

R ^d is hydrogen, C1-C6 alkyl, ^Cyc1 or ^hetCyc1 ; and

R ^e is hydrogen or C1-C6 alkyl.

In one embodiment of formula IA, ^R is

R ^c is hydrogen, C1-C6 alkyl, fluoro C1-C6 alkyl, C2-C6 alkenyl, Cyc ¹ , hetCyc ¹ or Ar ¹ ;

R ^d is C1-C6 alkyl, Cyc ¹ or hetCyc ¹ ; and

R ^e is hydrogen or C1-C6 alkyl.

In one embodiment of Formula IA, R ¹ is a triazolyl ring optionally substituted with a substituent selected from C 1 -C 6 alkyl and Cyc ¹ .

In one embodiment of formula IA, ^R is

Wherein R ^f is hydrogen, C1-C6 alkyl or Cyc ¹ .

In one embodiment of formula I: R ¹ is 3-isoxazolyl, which is substituted by 1 substituent independently selected from the following: C1-C6 alkyl, unsubstituted Cyc ¹ and unsubstituted hetCyc ¹ ; R ² is C1-C6 alkyl; and R ^y is hydrogen.

In one embodiment of formula I: R ¹ is 3-isoxazolyl, which is substituted by 2 substituents independently selected from: halogen, C1-C6 alkyl, unsubstituted Cyc ¹ and unsubstituted Substituted hetCyc ¹ ; R ² is C1-C6 alkyl; and R ^y is hydrogen.

Compounds of formula I include pharmaceutically acceptable salts thereof. In addition, the compounds of formula I also include other salts of such compounds, which are not necessarily pharmaceutically acceptable salts and are suitable for the preparation and/or purification of compounds of formula I and/or the separation of enantiomers of compounds of formula I body intermediates. Non-limiting examples of pharmaceutically acceptable salts of compounds of formula I include trifluoroacetate. In one embodiment, the compound of formula I includes trifluoroacetic acid and dihydrochloride.

It is further understood that compounds of formula I or salts thereof may be isolated in the form of solvates, and accordingly, any such solvates are included within the scope of the present invention. For example, compounds of formula I and salts thereof can exist in undissolved forms as well as dissolved forms with pharmaceutically acceptable solvents such as water, ethanol and the like.

In one embodiment, the compound of formula I includes the compounds of Examples 1-34 as well as stereoisomers and pharmaceutically acceptable salts and solvates thereof. In one embodiment, the compound of Examples 1-34 is in free base form. In one embodiment, the compound of Examples 1-34 is a trifluoroacetate salt.

The term "pharmaceutically acceptable" means that the compound or salt or composition thereof is chemically and/or toxicologically compatible with the other ingredients making up the formulation and/or the patient treated therewith.

The compounds provided herein may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. That is, especially when referred to with respect to a compound of formula I, an atom includes all isotopes and mixtures of isotopes (either naturally occurring or synthetically prepared) of that atom in natural abundance or in isotopically enriched form. For example, when referring to hydrogen, it should be understood to mean ¹ H, ² H, ³ H or a mixture thereof; when referring to carbon, it should be understood to mean ¹¹ C, ¹² C, ¹³ C, ¹⁴ C or a mixture thereof ; When referring to nitrogen, it should be understood to mean ¹³ N, ¹⁴ N, ¹⁵ N or a mixture thereof; when referring to oxygen, it should be understood to mean ¹⁴ O, ¹⁵ O, ¹⁶ O, ¹⁷ O, ¹⁸ O or a mixture thereof ; and when fluorine is mentioned, it is understood to mean ¹⁸ F, ¹⁹ F or a mixture thereof. The compounds provided herein therefore also include compounds having one or more isotopes of one or more atoms, and mixtures thereof, including radioactive compounds in which one or more non-radioactive atoms have been replaced by one of its radioactively enriched isotopes. Radiolabeled compounds are useful as therapeutic agents, such as cancer therapeutics; research reagents, such as analytical reagents; and diagnostic agents, such as in vivo imaging agents. All isotopic variations of the compounds provided herein, whether radioactive or not, are intended to be encompassed within the scope of the invention.

For purposes of illustration, Schemes 1-5 show general methods for the preparation of the compounds provided herein as well as key intermediates. For a more detailed description of the individual reaction steps, see the Examples section below. Those skilled in the art will appreciate that other synthetic routes may also be used to synthesize the compounds of the present invention. Although specific starting materials and reagents are described in the schemes and discussed below, other starting materials and reagents can be readily substituted to provide a variety of derivatives and/or reaction conditions. In addition, various compounds prepared by the methods described below can be further modified in accordance with the present invention using conventional chemistry well known to those skilled in the art.

Scheme 1 shows a method for preparing a compound of formula I, wherein R ¹ is an isoxazolyl ring, R ^b is Br, I, hetAr ¹ , Ar ¹ , hetCyc ¹ or Cyc ¹ , R ^y is hydrogen, and R ^a and R ² is as defined for formula I. Commercially available compounds of formula 1, wherein ^Ry is hydrogen, can be reacted with alkyllithium and DMF to give compound 2. The ring nitrogen of compound 2 can be protected to give compound 3 with a standard nitrogen protecting group P ¹ , such as benzenesulfonate. Compound 3 can be reacted with hydroxylamine hydrochloride to give compound 4. Ring closure of the oxime group of compound 4 can be achieved by treating compound 4 with a compound of formula HC≡CR ^a to give compound 5. Compound 5 can be reacted with N-bromosuccinimide or N-iodosuccinimide to give compound 6, wherein X is Br or I, respectively. The chloro group of compound 6 can be replaced with an amine group by treating compound 6 with ammonia, after removal of the amine protecting group, resulting in formula I, wherein ^R is hydrogen and R is ^Br or I.

Wherein R ^b is Br or I and ^R is C1-C6 alkyl, fluoro C1-C6 alkyl, cyano C1-C6 alkyl, hydroxyl C1-C6 alkyl, C3-C6 cycloalkyl or (C3-C6 Cycloalkyl) C1-C6 alkyl- compound of formula I can be obtained by combining a compound of formula I wherein R ^b is Br or I and ^R2 is hydrogen with formula ^R2 -X (wherein ^R2 is C1-C6 alkane base, fluoro C1-C6 alkyl, cyano C1-C6 alkyl, hydroxy C1-C6 alkyl, C3-C6 cycloalkyl or (C3-C6 cycloalkyl) C1-C6 alkyl-) reagent reaction to preparation.

酸酯化合物反應，其中R^b 為hetAr¹ 、Ar¹ 、hetCyc¹ 或Cyc¹ ，其中hetAr¹ 及Ar¹ 如關於式I所定義，hetCyc¹ 如關於式I所定義，限制條件為hetCyc¹ 為部分不飽和雜環，且Cyc¹ 如關於式I所定義，限制條件為Cyc¹ 為部分不飽和C3-C6環烷基環，且各R'獨立地為H或C1-C6烷基，或各R'與其所連接之原子共同形成視情況經1-4個選自(C1-C3烷基)之取代基取代之5-6員環，以產生其中R² 為C1-C6烷基、氟C1-C6烷基、氰基C1-C6烷基、羥基C1-C6烷基、C3-C6環烷基或(C3-C6環烷基)C1-C6烷基-且R^b 為hetAr¹ 、Ar¹ 、hetCyc¹ 或Cyc¹ 之式I化合物，其中hetAr¹ 及Ar¹ 如關於式I所定義，hetCyc¹ 如關於式I所定義，限制條件為hetCyc¹ 為部分不飽和雜環，且Cyc¹ 如關於式I所定義，限制條件為Cyc¹ 為部分不飽和C3-C6環烷基環。As shown in Scheme 1, suitable palladium-catalyzed cross-coupling reaction conditions may be used, such as Suzuki coupling reaction conditions (e.g., in dioxane at elevated temperature, a palladium catalyst and optionally a coordination body and in the presence of inorganic bases (such as Pd(PPh ₃ ) ₄ and Na ₂ CO ₃ ) such that X=R ^b =Br or I and R ² is C1-C6 alkyl, fluoro C1-C6 alkyl, cyanide C1-C6 alkyl, hydroxy C1-C6 alkyl, C3-C6 cycloalkyl or (C3-C6 cycloalkyl) C1-C6 alkyl- compound of formula I is further combined with formula R ^b -B (OR' ) of ₂

Ester compound reaction, wherein R ^b is hetAr ¹ , Ar ¹ , hetCyc ¹ or Cyc ¹ , wherein hetAr ¹ and Ar ¹ are as defined for formula I, and hetCyc ¹ is as defined for formula I, with the proviso that hetCyc ¹ is a moiety Unsaturated heterocycle, and Cyc ¹ is as defined for formula I, with the proviso that Cyc ¹ is a partially unsaturated C3-C6 cycloalkyl ring, and each R' is independently H or C1-C6 alkyl, or each R ' together with the atoms to which it is attached form a 5-6 membered ring optionally substituted by 1-4 substituents selected from (C1-C3 alkyl), to produce wherein R ² is C1-C6 alkyl, fluorine C1- C6 alkyl, cyano C1-C6 alkyl, hydroxy C1-C6 alkyl, C3-C6 cycloalkyl or (C3-C6 cycloalkyl) C1-C6 alkyl- and R ^b is hetAr ¹ , Ar ¹ , A compound of formula I of hetCyc ¹ or Cyc ¹ , wherein hetAr ¹ and Ar ¹ are as defined for formula I, hetCyc ¹ is as defined for formula I, with the proviso that hetCyc ¹ is a partially unsaturated heterocyclic ring, and Cyc ¹ is as defined for formula I As defined by I, the restriction is that Cyc ¹ is a partially unsaturated C3-C6 cycloalkyl ring.

Alternatively, as shown in Scheme 1, suitable palladium-catalyzed cross-coupling reaction conditions can be used, such as Stille coupling reaction conditions (for example, in the presence of a palladium catalyst and a ligand such as _PdCl2 [P(cy ) ₃ ] ₂ ) in the presence and optionally in the presence of cesium fluoride), such that X=R ^b =Br or I and R ² is C1-C6 alkyl, fluoroC1-C6 alkyl, cyano C1-C6 Alkyl, hydroxy C1-C6 alkyl, C3-C6 cycloalkyl or (C3-C6 cycloalkyl) C1-C6 alkyl- compound of formula I with formula R ^b -Sn (C1-C6 alkyl) ₃ The organotin compound reaction, wherein R ^b is hetAr ¹ , Ar ¹ , hetCyc ¹ or Cyc ¹ , wherein hetAr ¹ and Ar ¹ are as defined for formula I, hetCyc ¹ is as defined for formula I, with the proviso that hetCyc ¹ is Partially unsaturated heterocycle, and Cyc ¹ is as defined for formula I, with the proviso that Cyc ¹ is a partially unsaturated C3-C6 cycloalkyl ring, to produce wherein ^R2 is C1-C6 alkyl, fluoroC1-C6 alkane group, cyano C1-C6 alkyl, hydroxy C1-C6 alkyl, C3-C6 cycloalkyl or (C3-C6 cycloalkyl) C1-C6 alkyl- and R ^b is hetAr ¹ , Ar ¹ , hetCyc ¹ or a compound of formula I of Cyc ¹ , wherein hetAr ¹ and Ar ¹ are as defined for formula I, hetCyc ¹ is as defined for formula I, with the proviso that hetCyc ¹ is a partially unsaturated heterocyclic ring, and Cyc ¹ is as defined for formula I Definition, with the restriction that Cyc ¹ is a partially unsaturated C3-C6 cycloalkyl ring.

Compounds of formula I may undergo further modification (ie, reaction with or treatment with suitable reagents) to yield other compounds of formula I. For example, a compound of formula I wherein hetCyc ¹ is a saturated heterocycle as defined for formula I or a compound of formula I wherein Cyc ¹ is a saturated C3-C6 cycloalkyl ring as defined for formula I can be obtained by Compounds of formula I wherein hetCyc ¹ is a partially unsaturated heterocycle or Cyc ¹ is a partially unsaturated C3-C6 cycloalkyl ring are prepared by subjecting them to standard olefin reduction conditions.

Scheme 2 shows a method for the preparation of compounds of formula I, wherein R ¹ is an isoxazole ring, R ^y is hydrogen, R ^b is ^hydrogen and Ra and R ² are as defined for formula I. Compound 5 (prepared as shown in Scheme 1), wherein ^Ry is hydrogen, ^Rb is hydrogen, ^Ra is as defined for formula I and ^P1 is a nitrogen protecting group such as benzenesulfonate, can be treated with ammonia to yield Compound 7. The amine protecting group ^P1 of compound 7 can be removed under standard conditions to yield compounds of formula I wherein ^R2 is hydrogen.

Alternatively, the nitrogen protecting group P ¹ in compound 5, wherein R ^a , R ^b , R ^y and P ¹ are as defined for scheme 2, can be removed. The resulting compound can be reacted with ammonium hydroxide to yield a compound of formula I wherein ^R2 is hydrogen.

A compound of formula I wherein ^Ry is hydrogen, ^Rb is hydrogen, ^R2 is hydrogen can be reacted with a reagent of formula ^R2 -X, wherein ^R2 is C1-C6 alkyl, fluoroC1-C6 alkyl, cyano C1-C6 alkyl, hydroxyC1-C6 alkyl, C3-C6 cycloalkyl or (C3-C6 cycloalkyl) C1-C6 alkyl- and X is halogen, to produce wherein R ² is C1-C6 alkane C1-C6 alkyl, cyano C1-C6 alkyl, hydroxy C1-C6 alkyl, C3-C6 cycloalkyl or (C3-C6 cycloalkyl) C1-C6 alkyl- compound of formula I.

之試劑反應，其中R^a1 、R^b1 、R^c1 及R^d1 中之每一者獨立地為氫或C1-C4烷基，限制條件為

具有2-6個碳原子，以產生式I化合物，其中R² 為

，其中R^a1 、R^b1 、R^c1 及R^d1 中之每一者獨立地為氫或C1-C4烷基，限制條件為

部分具有2-6個碳原子。Alternatively, ^a compound of formula I wherein R ^a is as defined for formula I, R ^y is hydrogen, R ^b is hydrogen and R is hydrogen may be combined with the formula

A reagent reaction wherein each of R ^a1 , R ^b1 , R ^c1 and R ^d1 is independently hydrogen or C1-C4 alkyl, provided that

having 2-6 carbon atoms, to produce compounds of formula I, wherein R ^is

, wherein each of R ^a1 , R ^b1 , R ^c1 and R ^d1 is independently hydrogen or C1-C4 alkyl, provided that

Some have 2-6 carbon atoms.

A compound of formula ^I wherein ^R is as defined for formula I, R is ^hydrogen , R is ^hydrogen and R is hydrogen can be reacted with a reagent of formula R ^-X , wherein ^R is C1-C6 alkyl , fluoro C1-C6 alkyl, cyano C1-C6 alkyl, hydroxy C1-C6 alkyl, Cyc ³ , (Cyc ³ ) C1-C6 alkyl-, hetCyc ² or (Ar ² ) C1-C6 alkyl- and X is a leaving atom (such as Br, Cl or I) or a leaving group (such as OTf, OTs or OMs) to produce wherein R ^is C1-C6 alkyl, fluoroC1-C6 alkyl, cyano C1-C6 Alkyl, hydroxyC1-C6alkyl, ^Cyc3 , ( ^Cyc3 )C1-C6alkyl-, ^hetCyc2 or ( ^Ar2 )C1-C6alkyl-, compounds of the formula I.

Scheme 3 shows a method for the preparation of compounds of formula I, wherein R ^y is hydrogen, ^Ra is Cyc ¹ , R ^b is hydrogen and R ¹ , R ² and Cyc ¹ are as defined for formula I. Commercially available compound 8 can be treated with an amine compound of formula ^R2 - _NH2 , wherein ^R2 is as defined for formula I, to give bicyclic compound 9. Compound 9 can be treated with POCl ₃ to give compound 10. Compound 11 can be produced by replacing the chlorine group of compound 10 with an amine group upon treatment of compound 10 with ammonium hydroxide. Compound 11 can be treated with hydroxylamine hydrochloride to give compound 12. Ring closure of the oxime group of compound 12 can be achieved by treating compound 12 with a reagent of formula R ^b C≡CR ^a , wherein R ^b is hydrogen and R ^a is as defined for formula I, to yield a compound of formula I, wherein R ¹ is an oxazolyl ring, R ^a is Cyc ¹ and R ^b is hydrogen.

Alternatively, compound 9 can be treated with N-iodosuccinimide to give compound 13. Compound 13 can be treated with ammonium hydroxide to give compound 14. Compound 14, wherein R ¹ is as defined for formula I, can be treated with borondioxine compound (a), to yield compounds of formula I, wherein R ¹ is as defined for formula I.

Alternatively, compound 14 can be treated with ethynyltrimethylsilane in the presence of copper and palladium catalysts to give compound 15. The silyl protecting group of compound 15 can be removed under standard conditions to give compound 16. Compound 16 can be reacted with azidotrimethylsilane to produce compounds of formula I, wherein R ¹ is an unsubstituted triazolyl ring.

As shown in scheme 3, the formula I compound wherein R ¹ is a triazolyl ring substituted by C1-C6 alkyl or C3-C6 cycloalkyl can be obtained by using a reagent of formula R ^f -X (wherein R ^f is C1-C6 alkyl or C3-C6 cycloalkyl and X is halogen) by treating a compound of formula I wherein ^R is an unsubstituted triazolyl ring.

酸酯化合物(其中R¹ 如關於式I所定義)處理化合物19以產生式I化合物。

Scheme 4 shows a method for the preparation of compounds of formula I, wherein ^Ry is hydrogen and ^R1 and ^R2 are as defined for formula I. Commercially available compound 17, wherein ^R2 is hydrogen and ^Ry is hydrogen, can be reacted with a reagent of formula ^R2 -X, wherein X is halogen and ^R2 is as defined for formula I, to give compound 13. Compound 13 can be reacted with a reagent of formula P ¹ —NH ₂ , where P ¹ is an amine protecting group, such as benzenesulfonate, to give compound 18. The amine protecting group of compound 18 can be removed under standard conditions to give compound 19. Suitable palladium-catalyzed cross-coupling reaction conditions can be used, such as Suzuki coupling reaction conditions (e.g. palladium at elevated temperature in dioxane in the presence of inorganic bases such as Pd(PPh ₃ ) _{4 and} Na ₂ CO ₃ ). Catalyst and the ligand selected as the case may be), with formula (a)

Compound 19 is treated with an acid ester compound wherein R ¹ is as defined for formula I to yield a compound of formula I.

Scheme 5 shows a method for the preparation of compounds of formula I, wherein R ¹ is an isoxazolyl ring, R ^y is HC(=O)- or HOCH ₂ -, R ^b is hydrogen and Ra ^and R ² are as for formula I defined. Commercially available compound 20 can be reacted with a reagent of formula ^R2 -X, wherein ^R2 is C1-C6 alkyl and X is halogen, in the presence of a base to give compound 21. Compound 21 can be reacted with hydroxylamine to give compound 22. Ring closure of the oxime group of compound 22 can be achieved by treating compound 22 ^with a compound of formula ^RbC≡CRa , wherein ^Ra is as defined for formula I and ^Rb is hydrogen, to give compound 23. Compound 23 was treated with LDA followed by addition of ethyl formate to give compound 24. Compound 24 can be treated with ammonium hydroxide to yield compounds of formula I wherein ^Ry is HC(=O)-.

Compounds of formula ^I wherein ^Ry is HOCH2- can be prepared by treating compounds of formula I wherein Ry is HC(=O)- with an aldehyde reducing agent such as sodium _borohydride .

經歷環加成，其中R^a 如關於式I所定義，以產生化合物28，其中R² 及R^a 如關於式I所定義或R² 為氮保護基。可將化合物28之酯基還原(例如用DIBAL)以產生化合物29。可使化合物29之醇部分氧化，接著所得醛可經歷烯烴化(例如維蒂希反應(Wittig reaction)或其變異體)，得到化合物30。可使化合物30與氫氧化銨反應，得到化合物31。化合物31之烯基部分可經歷二羥基化(例如用四氧化鋨(OsO₄ ))以在移除任何保護基(若存在)之後產生式I化合物，其中R² 及R^a 如關於式I所定義。

Scheme 6 shows a method for the preparation of compounds of formula I, wherein R ^is an isoxazolyl ring, ^R is hydrogen, R ^is -CH(OH) _CH (OH) and R ^{and Ra} are as for formula I defined. Compound 25 can be functionalized at the pyrrolo nitrogen to give compound 26, wherein ^R2 is C1-C6 alkyl, fluoroC1-C6 alkyl, cyano C1-C6 alkyl, hydroxyC1-C6 alkyl, ^Ar2 , (Ar ² )C1-C6alkyl-, ^hetCyc2 , ^Cyc3 or ( ^Cyc3 )C1-C6alkyl-, wherein ^Ar2 , ^Cyc3 and ^hetCyc2 are as defined for formula I. For example, compound 25 can be reacted with a reagent of formula ^R2 -X, wherein X is a leaving atom (such as Br, Cl, I) or a leaving group (such as OTs, OMs, or OTf); and R is ^C1 -C6 Alkyl, fluoro C1-C6 alkyl, cyano C1-C6 alkyl, hydroxy C1-C6 alkyl, (Ar ² ) C1-C6 alkyl-, hetCyc ² , Cyc ³ or (Cyc ³ ) C1-C6 alkane Group-, wherein Ar ² , Cyc ³ and hetCyc ² are as defined for formula I. Alternatively, compound 25 can be reacted with a reagent of formula ^Ar2 -B(OH) ₂ , wherein ^Ar2 is as defined for formula I, to give compound 26, wherein ^R2 is ^Ar2 as defined for formula I. Compound 26 can be converted to oxime 27 after condensation with hydroxylamine. Alternatively, compound 25, wherein the pyrrolo nitrogen is optionally protected with a nitrogen protecting group, can be reacted with hydroxylamine to provide compound 27, wherein ^R2 is a nitrogen protecting group or hydrogen. Compound 27 can be used with

undergoes cycloaddition, wherein ^Ra is as defined for formula I, to give compound 28, wherein R ^{and Ra} are as defined for formula I or ^R is a nitrogen protecting group. The ester group of compound 28 can be reduced (eg, with DIBAL) to give compound 29. The alcohol of compound 29 can be partially oxidized, and the resulting aldehyde can then undergo olefination (eg, the Wittig reaction or variants thereof) to afford compound 30. Compound 30 can be reacted with ammonium hydroxide to give compound 31. The alkenyl moiety of compound 31 can undergo dihydroxylation (e.g. with osmium tetroxide (OsO ₄ )) to yield a compound of formula I after removal of any protecting groups, if present, wherein R ^{and Ra} are as described for formula I definition.

Scheme 7 shows a method for the preparation of compounds of formula I, wherein R ¹ is pyrazolyl, wherein R ^c is C1-C6 alkyl, R ² is as defined for formula I and R ^y is —CH ₂ NH ₂ . Compound 32 can be functionalized at the pyrrolo nitrogen to give compound 33, wherein ^R2 is C1-C6 alkyl, fluoroC1-C6 alkyl, cyano C1-C6 alkyl, hydroxyC1-C6 alkyl, ^Ar2 , (Ar ² )C1-C6alkyl-, ^hetCyc2 , ^Cyc3 or ( ^Cyc3 )C1-C6alkyl-, wherein ^Ar2 , ^Cyc3 and ^hetCyc2 are as defined for formula I. For example, compound 32 can be reacted with a reagent of formula ^R2 -X or ^R2 -OH, wherein X is a leaving atom (such as a halogen such as Br) or a leaving group (such as OTs, OMs or OTf); and ^R2 C1-C6 alkyl, fluoro C1-C6 alkyl, cyano C1-C6 alkyl, hydroxyl C1-C6 alkyl, (Ar ² ) C1-C6 alkyl-, hetCyc ² , Cyc ³ , (Cyc ³ ) C1-C6 alkyl- or nitrogen protecting group, wherein Ar ² , Cyc ³ and hetCyc ² are as defined for formula I. Alternatively, compound 32 can be reacted with a reagent of formula ^Ar2 -B(OH) ₂ , wherein ^Ar2 is as defined for formula I, to give compound 33, wherein ^R2 is ^Ar2 . The ester group in compound 33 can be reduced (eg, with DIBAL) to give compound 34, followed by iodination with N-iodosuccinimide to give compound 35. The alcohol group of compound 35 can be protected with a suitable hydroxyl protecting group such as tert-butyldimethylsilyl (TBS) to give compound 36, which can be converted to compound 37 after treatment with ammonium hydroxide. Compound 37 can undergo palladium-catalyzed cross-coupling with reagent 38, wherein R ^c is C1-C6 alkyl, under standard conditions (eg, ( _PPh3 ) _2Pd (II) _Cl2 in the presence of an inorganic base) to give Compound 39. The hydroxyl protecting group on compound 39 can be removed under standard conditions to give compound 40, and the alcohol can then be converted to the azide moiety (eg, with DPPA) to give compound 41. The azido group of compound 41 can be reduced to give compound 42. The amine protecting group P ⁵ on compound 42 can be removed, after optional removal of any remaining protecting groups (if present), to give a compound of formula I, wherein R ¹ is pyrazolyl, wherein ^R is C1-C6 alkyl and R ² is as defined for formula I.

Scheme 8 shows a process for the preparation of compounds of formula I, wherein R ¹ is isoxazolyl, wherein R ^a is as defined for formula I; and R ² is Ar ² , hetCyc ² or Cyc ³ , wherein Cyc ³ is unsubstituted The C3-C6 cycloalkyl. Compound 43 can be prepared using methods similar to those described for the preparation of compound 5 in Scheme 2, wherein P ¹ is a nitrogen protecting group; and R ^a is as defined for formula I. The nitrogen protecting group P ¹ of 43 can be removed under standard conditions to give compound 44. After reaction with a reagent of formula R ² -OH, wherein R ² is hetCyc ² or Cyc ³ as defined for formula I, wherein Cyc ³ is an unsubstituted C3-C6 cycloalkyl (for example in Mitsunobu reaction (Mitsunobu reaction) conditions, such as triphenylphosphine and DIAD), compound 44 can be converted into a compound of formula I to produce a compound of formula I wherein R ² is hetCyc ² or Cyc ³ , wherein Cyc ³ is an unsubstituted C3- C6 cycloalkyl. Alternatively compound 44 can undergo a metal-catalyzed (eg copper-catalyzed) cross-coupling with a reagent of formula R ² —B(OR′) ₂ under standard conditions, wherein R ² is Ar ² as defined for formula I; and each R' is independently H or C1-C6 alkyl, or each R' and the atom to which it is connected together form a 5-6 membered ring optionally substituted by 1-4 substituents selected from (C1-C3 alkyl) , to produce a compound of formula I wherein R ² is Ar ² .

Scheme 9 shows a method for the preparation of compounds of formula I, wherein R ¹ is isoxazolyl, wherein R ^a is as defined for formula I, and R ^b is hetAr ¹ , Ar ¹ , hetCyc ¹ or Cyc ¹ , wherein hetAr ¹ and Ar ¹ is as defined for formula I, hetCyc ¹ is as defined for formula I, with the proviso that hetCyc ¹ is a partially unsaturated heterocycle, and Cyc ¹ is as defined for formula I, with the proviso that Cyc ¹ is partially unsaturated C3-C6 cycloalkyl ring; R ² is as defined for formula I; and R ^y is C1-C6 alkyl. Compound 44 can undergo metal-hydrogen exchange (e.g. with n-butyllithium), wherein R ^is as defined for formula I; ^R is as defined for formula I, with the proviso that R ^is not hydrogen or ^R is nitrogen protected The resulting anionic intermediate can then be captured by a reagent of the formula (C1-C6 alkyl)-X, where X is a leaving atom (such as Cl, Br or I) or a leaving group (such as OTf, OTs or OMs) to produce Compound 45. Compound 45 can undergo halogenation (eg, with N-iodosuccinimide) to afford compound 46, wherein X is Br or I. Treatment of compound 46 with ammonium hydroxide can yield compound 47. Under standard conditions (for example, in the presence of a palladium catalyst and optionally a ligand, and in the presence of an inorganic base), 47 and a reagent of the formula R ^b -Sn(C1-C6 alkyl) ₃ (wherein R ^b is hetAr ¹ , Ar ¹ , hetCyc ¹ or Cyc ¹ , wherein hetAr ¹ and Ar ¹ are as defined for formula I, hetCyc ¹ is as defined for formula I, with the proviso that hetCyc ¹ is a partially unsaturated heterocyclic ring, and Cyc ¹ is as defined for As defined with respect to Formula I, palladium-catalyzed cross-coupling with the proviso that Cyc ¹ is a partially unsaturated C3-C6 cycloalkyl ring) can yield compounds of Formula I after removal of any protecting groups.

As used herein, the term "amine protecting group" refers to a derivative of a group commonly used to block or protect an amine group while allowing other functional groups of the compound to react. Examples of protecting groups suitable for any of the methods described herein include carbamate groups, amides, alkyl and aryl groups, benzyl and substituted benzyl groups, imines, and various N-heteroatom derivatives which can be removed to regenerate the desired amine group. Non-limiting examples of amine protecting groups are 2,4-dimethoxybenzyl (DMB), acetyl, trifluoroacetyl, tert-butoxycarbonyl ("Boc"), benzyloxy Carbonyl (“CBz”) and 9-fenylmethyleneoxycarbonyl (“Fmoc”). Further examples of these and other protecting groups are found in TW Greene et al . Greene 's Protective Groups in Organic Synthesis . New York: Wiley Interscience, 2006.

The nitrogen atoms in the compounds described in any of the above methods can be protected with any convenient nitrogen protecting group, for example in Greene and Wuts eds., "Protecting Groups in Organic Synthesis", 2nd Ed., New York; John Wiley & Sons, Inc., described in 1991. Examples of nitrogen protecting groups include acyl and alkoxycarbonyl groups such as tert-butoxycarbonyl (BOC), phenoxycarbonyl and [2-(trimethylsilyl)ethoxy]methyl (SEM).

The hydroxy group may be protected with any convenient hydroxy protecting group, for example as described in T. W. Greene et al., Greene's Protective Groups in Organic Synthesis. New York: Wiley Interscience, 2006. Examples include benzyl, trityl, silyl ethers and the like.

Accordingly, further provided herein is a process for the preparation of a compound of formula I, or a pharmaceutically acceptable salt thereof, comprising:

(a) For compounds of formula I satisfying the following conditions: wherein R ² is hydrogen, R ^y is hydrogen and R ¹ is

wherein R ^a is as defined for formula I and X = R ^b = Br or I, such that a compound of formula

wherein ^Ry is hydrogen, X= ^Rb =Br or I, ^Ra is as defined for formula I and ^P1 is a nitrogen protecting group, reacted with ammonia, followed by removal of the nitrogen protecting group; or

(b) For compounds of formula I satisfying the following conditions: wherein R ² is C1-C6 alkyl, fluoro C1-C6 alkyl, cyano C1-C6 alkyl, hydroxy C1-C6 alkyl, C3-C6 cycloalkyl or (C3-C6cycloalkyl)C1-C6alkyl-, R ^y is hydrogen and R ¹ is

wherein X = R ^b = Br or I and R ^a is as defined for formula I, such that a compound of formula

wherein X= ^Rb =Br or I and ^Ra is as defined for formula I, reacted with a compound of formula ^R2 -X, wherein ^R2 is C1-C6 alkyl, fluoroC1-C6 alkyl, cyano C1 -C6 alkyl, hydroxy C1-C6 alkyl, C3-C6 cycloalkyl or (C3-C6 cycloalkyl) C1-C6 alkyl-; or

(c) For the compound of formula I satisfying the following conditions: wherein R ² is C1-C6 alkyl, fluoro C1-C6 alkyl, cyano C1-C6 alkyl, hydroxy C1-C6 alkyl, C3-C6 cycloalkyl or (C3-C6cycloalkyl)C1-C6alkyl-, R ^y is hydrogen and R ¹ is

wherein R ^b is hetAr ¹ , Ar ¹ , hetCyc ¹ or Cyc ¹ , wherein hetAr ¹ and Ar ¹ are as defined for formula I, and hetCyc ¹ is as defined for formula I, with the proviso that hetCyc ¹ is a partially unsaturated heterocycle, and Cyc ¹ is as defined for formula I, with the proviso that Cyc ¹ is a partially unsaturated C3-C6 cycloalkyl ring, and R ^a is as defined for formula I, such that a compound of formula R ^b -B(OR') ₂ Compound (wherein R ^b is hetAr ¹ , Ar ¹ , hetCyc ¹ or Cyc ¹ , wherein hetAr ¹ and Ar ¹ are as defined for formula I, hetCyc ¹ is as defined for formula I, with the proviso that hetCyc ¹ is a partially unsaturated hetero ring, and Cyc ¹ is as defined for formula I, with the proviso that Cyc ¹ is a partially unsaturated C3-C6 cycloalkyl ring, and each R' is independently H or C1-C6 alkyl, or each R' is associated with its Atoms connected together form a 5-6 membered ring optionally substituted by 1-4 substituents selected from (C1-C3 alkyl) and a corresponding compound with the following formula in a palladium catalyst and a ligand selected as the case may be react in the presence and presence of an inorganic base

where X is Br or I; or

(d) For compounds of formula I satisfying the following conditions: wherein R ² is C1-C6 alkyl, fluoro C1-C6 alkyl, cyano C1-C6 alkyl, hydroxy C1-C6 alkyl, C3-C6 cycloalkyl Or (C3-C6 cycloalkyl) C1-C6 alkyl-, R ^y is hydrogen, R ¹ is

Here R ^b is hetAr ¹ , Ar ¹ , hetCyc ¹ or Cyc ¹ , wherein hetAr ¹ and Ar ¹ are as defined for formula I and hetCyc ¹ is as defined for formula I, with the proviso that hetCyc ¹ is a partially unsaturated heterocycle , and Cyc ¹ is as defined for formula I, with the proviso that Cyc ¹ is a partially unsaturated C3-C6 cycloalkyl ring, and R ^a is as defined for formula I, so that it has the formula R ^b -Sn (C1-C6 alkane A compound of ₃ (wherein R ^b is hetAr ¹ , Ar ¹ , hetCyc ¹ or Cyc ¹ , wherein hetAr ¹ and Ar ¹ are as defined for formula I, hetCyc ¹ is as defined for formula I, with the proviso that hetCyc ¹ is Partially unsaturated heterocyclic ring, and Cyc ¹ is as defined for formula I, with the proviso that Cyc ¹ is a partially unsaturated C3-C6 cycloalkyl ring) with the corresponding compound of the formula on palladium catalyst and optional coordination In the presence of the body and the reaction in the presence of an inorganic base

where X is Br or I; or

(e) For compounds of formula I satisfying the following conditions: wherein R ² is C1-C6 alkyl, fluoro C1-C6 alkyl, cyano C1-C6 alkyl, hydroxy C1-C6 alkyl, C3-C6 cycloalkyl Or (C3-C6 cycloalkyl) C1-C6 alkyl-, R ^y is hydrogen, R ¹ is

wherein R ^b is hetAr ¹ , Ar ¹ , hetCyc ¹ or Cyc ¹ , wherein hetAr ¹ and Ar ¹ are as defined for formula I, and hetCyc ¹ is as defined for formula I, with the proviso that hetCyc ¹ is a saturated heterocycle, and Cyc ¹ as defined for formula I, with the proviso that Cyc ¹ is a saturated C3-C6 cycloalkyl ring, and R ^a is as defined for formula I, a compound of the formula is treated under olefin reducing conditions

Wherein ^R2 is C1-C6 alkyl, fluoro C1-C6 alkyl, cyano C1-C6 alkyl, hydroxyl C1-C6 alkyl, C3-C6 cycloalkyl or (C3-C6 cycloalkyl)C1-C6 Alkyl-, R ^y is hydrogen, R ^b is hetAr ¹ , Ar ¹ , hetCyc ¹ or Cyc ¹ , wherein hetAr ¹ and Ar ¹ are as defined for formula I, hetCyc ¹ is as defined for formula I, with the proviso that hetCyc ¹ is a partially unsaturated heterocyclic ring, and Cyc ¹ is as defined for formula I, with the proviso that Cyc ¹ is a partially unsaturated C3-C6 cycloalkyl ring, and ^Ra is as defined for formula I; or

f) For the compound of formula I satisfying the following conditions: wherein R ^y is hydrogen, R ² is C1-C6 alkyl, fluorine C1-C6 alkyl, cyano C1-C6 alkyl, hydroxyl C1-C6 alkyl, Cyc ³ , (Cyc ³ ) C1-C6 alkyl-, hetCyc ² or (Ar ² ) C1-C6 alkyl-, wherein Cyc ³ , hetCyc ² and Ar ¹ are as defined for formula I, and R ¹ is

wherein R ^b is hydrogen, and R ^a is as defined for formula I, such that a compound of formula

Here ^Ry is hydrogen, ^Rb is hydrogen, and ^Ra is as defined for formula I, reacted with a reagent of formula ^R2 -X, wherein ^R2 is C1-C6 alkyl, fluoroC1-C6 alkyl, Cyano C1-C6 alkyl, hydroxy C1-C6 alkyl, Cyc ³ , (Cyc ³ ) C1-C6 alkyl-, hetCyc ² or (Ar ² ) C1-C6 alkyl-, wherein Cyc ³ , hetCyc ² and Ar ^is as defined for formula I, and X is a leaving atom or leaving group; or

(g) For compounds of formula I satisfying the following conditions: wherein R ^y is hydrogen, R ² is as defined for formula I, and R ¹ is

wherein R ^b is hydrogen, and R ^a is as defined for formula I, such that a compound of formula

wherein R ^y is hydrogen and R ² is as defined for formula I, reacted with a reagent of formula R ^b C≡CR ^a , wherein R ^b is hydrogen and R ^a is as defined for formula I; or

(h) For compounds of formula I where ^R is hydrogen ^and R and ^R are as defined for formula I, such that a compound of formula

wherein ^Ry is hydrogen and ^R2 is as defined in formula I, reacted with a reagent having the formula

wherein ^R is as defined for formula I; or

(i) For compounds of formula I where ^R is an unsubstituted triazolyl ring, ^R is hydrogen and ^R is as defined for formula I, such that a compound of formula

react with azidotrimethylsilane; or

(j) For compounds of formula I satisfying the following conditions: wherein ^R is a triazolyl ring substituted by C1-C6 alkyl or C3-C6 cycloalkyl, ^Ry is hydrogen and ^R2 is as defined for formula I, make a compound of the formula

wherein ^R is hydrogen and ^R is as defined for formula I, reacted with a reagent of formula R ^-X , wherein ^R is C1-C6 alkyl or C3-C6 cycloalkyl and X is halogen; or

(k) For compounds of formula I satisfying the following conditions: wherein R ^y is HC(=O)-, R ^b is hydrogen, R ² is as defined for formula I, R ¹ is

wherein R ^b is hydrogen and R ^a is as defined for formula I, such that a compound of formula

wherein R is ^{hydrogen and} R and ^R are as defined for formula I, reacted with ammonium hydroxide; or

(l) For compounds of formula I satisfying the following conditions: wherein R ^y is HOCH ₂ -, R ^b is hydrogen, R ² is as defined for formula I, and R ¹ is

wherein R ^b is hydrogen and R ^a is as defined for formula I, such that a compound of formula

wherein R ^{is hydrogen} and R and ^R are as defined for formula I, reacted with an aldehyde reducing agent;

(m) For a compound of formula I satisfying the following conditions: wherein R ² is hetCyc ² or Cyc ³ , wherein Cyc ³ is an unsubstituted C3-C6 cycloalkyl group, R ^y is hydrogen and R ¹ is

wherein R ^a is as defined for formula I, such that a compound of the formula

wherein R ^a is as defined for formula I, reacted with a compound of formula R ² —OH, wherein R ² is hetCyc ² or Cyc ³ as defined for formula I, wherein Cyc ³ is an unsubstituted C3-C6 ring alkyl, followed by reaction with ammonium hydroxide; or

(n) For a compound of formula I satisfying the following conditions: wherein R ² is Cyc ³ or Ar ¹ , R ^y is hydrogen and R ¹ is

wherein R ^a is as defined for formula I, is a compound of formula R ² -B(OR') ₂ , wherein R ² is Cyc ³ or Ar ¹ , wherein Cyc ³ and Ar ¹ are as defined for formula I, and each R' is independently H or C1-C6 alkyl, or each R' and the atom to which it is connected together form a 5-6 membered ring optionally substituted by 1-4 substituents selected from (C1-C3 alkyl) , react with the corresponding compound having the formula

wherein ^Ra is as defined for formula I, followed by reaction with ammonium hydroxide; or

，其中R^a1 、R^b1 、R^c1 及R^d1 中之每一者獨立地為氫或C1-C4烷基，限制條件為

部分具有2-6個碳原子，R^y 為氫且R¹ 為

(o) For compounds of formula I satisfying the following conditions: wherein R ² is

, wherein each of R ^a1 , R ^b1 , R ^c1 and R ^d1 is independently hydrogen or C1-C4 alkyl, provided that

The moiety has 2-6 carbon atoms, R ^y is hydrogen and R ¹ is

wherein R ^a is as defined for formula I, such that a compound of the formula

之化合物反應，其中R^a1 、R^b1 、R^c1 及R^d1 中之每一者獨立地為氫或C1-C4烷基，限制條件為

具有2-6個碳原子；或where R ^a is as defined for formula I, and has the formula

wherein each of R ^a1 , R ^b1 , R ^c1 and R ^d1 is independently hydrogen or C1-C4 alkyl, provided that

has 2-6 carbon atoms; or

(p) For compounds of formula I satisfying the following conditions: wherein R ² is as defined for formula I, R ^y is hydrogen and R ¹ is

wherein ^Ra is as defined for formula I, dihydroxylates the alkenyl moiety in compounds of the formula

wherein R ^is as defined for formula I; and ^R is as defined for formula I; or

(q) For compounds of formula I satisfying the following conditions: wherein R ² is as defined for formula I, R ^y is C1-C6 alkyl and R ¹ is

wherein R ^a is as defined for formula I; R ^b is defined as hetAr ¹ , Ar ¹ , hetCyc ¹ or Cyc ¹ , wherein hetAr ¹ and Ar ¹ are as defined for formula I, and hetCyc ¹ is as defined for formula I, with the restriction that hetCyc ¹ is a partially unsaturated heterocyclic ring, and Cyc ¹ is as defined for formula I, with the proviso that Cyc ¹ is a partially unsaturated C3-C6 cycloalkyl ring, and Ra ^is as defined for formula I, such that the formula R ^b -Sn(C1-C6 alkyl) ₃ compound (wherein R ^b is hetAr ¹ , Ar ¹ , hetCyc ¹ or Cyc ¹ , wherein hetAr ¹ and Ar ¹ are as defined for formula I, and hetCyc ¹ is as defined for formula I Definition, with the proviso that hetCyc ¹ is a partially unsaturated heterocyclic ring, and Cyc ¹ is as defined for formula I, with the proviso that Cyc ¹ is a partially unsaturated C3-C6 cycloalkyl ring) with the corresponding compound of the formula Reaction in the presence of a catalyst and an optional ligand and in the presence of an inorganic base

wherein X is Br or I; ^Ra is as defined for formula I; ^R is as defined for formula I; and ^R is C1-C6 alkyl; or

(r) For compounds of formula I where R ² is as defined for formula I, R ^y is CH ₂ NH ₂ and R ¹ is

Where R ^c is a C1-C6 alkyl group, so that the azido group in the following formula is partially reduced

wherein Pg is an amino protecting group; R ^is as defined for formula I; and ^R is C1-C6 alkyl, followed by removal of the amino protecting group;

and

Any protecting groups are removed, and pharmaceutically acceptable salts thereof are formed as appropriate.

In some embodiments, the present invention provides a process for the preparation of a compound of formula I as defined herein, or a pharmaceutically acceptable salt thereof, comprising:

(a) For compounds of formula I satisfying the following conditions: wherein R ² is hydrogen, R ^y is hydrogen, R ¹ is

wherein R ^a is as defined for formula I and X = R ^b = Br or I, such that a compound of formula

wherein ^Ry is hydrogen, X= ^Rb =Br or I, ^Ra is as defined for formula I and ^P1 is a nitrogen protecting group, reacted with ammonia, followed by removal of the nitrogen protecting group; or

(b) For compounds of formula I satisfying the following conditions: wherein R ² is C1-C6 alkyl, fluoro C1-C6 alkyl, cyano C1-C6 alkyl, hydroxy C1-C6 alkyl, C3-C6 cycloalkyl Or (C3-C6 cycloalkyl) C1-C6 alkyl-, R ^y is hydrogen, R ¹ is

wherein X = R ^b = Br or I and R ^a is as defined for formula I, such that a compound of formula

wherein X= ^Rb =Br or I and ^Ra is as defined for formula I, reacted with a compound of formula ^R2 -X, wherein ^R2 is C1-C6 alkyl, fluoroC1-C6 alkyl, cyano C1 -C6 alkyl, hydroxy C1-C6 alkyl, C3-C6 cycloalkyl or (C3-C6 cycloalkyl) C1-C6 alkyl-; or

其中R^b 為hetAr¹ 、Ar¹ 、hetCyc¹ 或Cyc¹ ，其中hetAr¹ 及Ar¹ 如關於式I所定義，hetCyc¹ 如關於式I所定義，限制條件為hetCyc¹ 為部分不飽和雜環，且Cyc¹ 如關於式I所定義，限制條件為Cyc¹ 為部分不飽和C3-C6環烷基環，且R^a 如關於式I所定義，使具有式R^b -B(OR')₂ 之化合物(其中R^b 為hetAr¹ 、Ar¹ 、hetCyc¹ 或Cyc¹ ，其中hetAr¹ 及Ar¹ 如關於式I所定義，hetCyc¹ 如關於式I所定義，限制條件為hetCyc¹ 為部分不飽和雜環，且Cyc¹ 如關於式I所定義，限制條件為Cyc¹ 為部分不飽和C3-C6環烷基環，且各R'獨立地為H或C1-C6烷基，或各R'與其所連接之原子共同形成視情況經1-4個選自(C1-C3烷基)之取代基取代之5-6員環)與具有下式之相應化合物在鈀催化劑及視情況選用之配位體存在下且在無機鹼存在下反應

(c) For the compound of formula I satisfying the following conditions: wherein R ² is C1-C6 alkyl, fluoro C1-C6 alkyl, cyano C1-C6 alkyl, hydroxy C1-C6 alkyl, C3-C6 cycloalkyl Or (C3-C6 cycloalkyl) C1-C6 alkyl-, R ^y is hydrogen, R ¹ is

wherein R ^b is hetAr ¹ , Ar ¹ , hetCyc ¹ or Cyc ¹ , wherein hetAr ¹ and Ar ¹ are as defined for formula I, and hetCyc ¹ is as defined for formula I, with the proviso that hetCyc ¹ is a partially unsaturated heterocycle, and Cyc ¹ is as defined for formula I, with the proviso that Cyc ¹ is a partially unsaturated C3-C6 cycloalkyl ring, and R ^a is as defined for formula I, such that a compound of formula R ^b -B(OR') ₂ Compound (wherein R ^b is hetAr ¹ , Ar ¹ , hetCyc ¹ or Cyc ¹ , wherein hetAr ¹ and Ar ¹ are as defined for formula I, hetCyc ¹ is as defined for formula I, with the proviso that hetCyc ¹ is a partially unsaturated hetero ring, and Cyc ¹ is as defined for formula I, with the proviso that Cyc ¹ is a partially unsaturated C3-C6 cycloalkyl ring, and each R' is independently H or C1-C6 alkyl, or each R' is associated with its Atoms connected together form a 5-6 membered ring optionally substituted by 1-4 substituents selected from (C1-C3 alkyl) and a corresponding compound with the following formula in a palladium catalyst and a ligand selected as the case may be react in the presence and presence of an inorganic base

where X is Br or I; or

其中R^b 為hetAr¹ 、Ar¹ 、hetCyc¹ 或Cyc¹ ，其中hetAr¹ 及Ar¹ 如關於式I所定義，hetCyc¹ 如關於式I所定義，限制條件為hetCyc¹ 為部分不飽和雜環，且Cyc¹ 如關於式I所定義，限制條件為Cyc¹ 為部分不飽和C3-C6環烷基環，且R^a 如關於式I所定義，使具有式R^b -Sn(C1-C6烷基)₃ 之化合物(其中R^b 為hetAr¹ 、Ar¹ 、hetCyc¹ 或Cyc¹ ，其中hetAr¹ 及Ar¹ 如關於式I所定義，hetCyc¹ 如關於式I所定義，限制條件為hetCyc¹ 為部分不飽和雜環，且Cyc¹ 如關於式I所定義，限制條件為Cyc¹ 為部分不飽和C3-C6環烷基環)與具有下式之相應化合物在鈀催化劑及視情況選用之配位體存在下且在無機鹼存在下反應

(d) For compounds of formula I satisfying the following conditions: wherein R ² is C1-C6 alkyl, fluoro C1-C6 alkyl, cyano C1-C6 alkyl, hydroxy C1-C6 alkyl, C3-C6 cycloalkyl Or (C3-C6 cycloalkyl) C1-C6 alkyl-, R ^y is hydrogen, R ¹ is

wherein R ^b is hetAr ¹ , Ar ¹ , hetCyc ¹ or Cyc ¹ , wherein hetAr ¹ and Ar ¹ are as defined for formula I, and hetCyc ¹ is as defined for formula I, with the proviso that hetCyc ¹ is a partially unsaturated heterocycle, and Cyc ¹ is as defined for formula I, with the proviso that Cyc ¹ is a partially unsaturated C3-C6 cycloalkyl ring, and R ^a is as defined for formula I, such that it has the formula R ^b -Sn(C1-C6 alkyl ) ₃ (wherein R ^b is hetAr ¹ , Ar ¹ , hetCyc ¹ or Cyc ¹ , wherein hetAr ¹ and Ar ¹ are as defined for formula I, hetCyc ¹ is as defined for formula I, with the proviso that hetCyc ¹ is a moiety Unsaturated heterocyclic ring, and Cyc ¹ is as defined for formula I, with the proviso that Cyc ¹ is a partially unsaturated C3-C6 cycloalkyl ring) with the corresponding compound of the following formula on a palladium catalyst and optionally a ligand react in the presence and presence of an inorganic base

where X is Br or I; or

(e) For compounds of formula I satisfying the following conditions: wherein R ² is C1-C6 alkyl, fluoro C1-C6 alkyl, cyano C1-C6 alkyl, hydroxy C1-C6 alkyl, C3-C6 cycloalkyl Or (C3-C6 cycloalkyl) C1-C6 alkyl-, R ^y is hydrogen, R ¹ is

wherein R ^b is hetAr ¹ , Ar ¹ , hetCyc ¹ or Cyc ¹ , wherein hetAr ¹ and Ar ¹ are as defined for formula I, and hetCyc ¹ is as defined for formula I, with the proviso that hetCyc ¹ is a saturated heterocycle, and Cyc ¹ as defined for formula I, with the proviso that Cyc ¹ is a saturated C3-C6 cycloalkyl ring, and R ^a is as defined for formula I, a compound of the formula is treated under olefin reducing conditions

Wherein ^R2 is C1-C6 alkyl, fluoro C1-C6 alkyl, cyano C1-C6 alkyl, hydroxyl C1-C6 alkyl, C3-C6 cycloalkyl or (C3-C6 cycloalkyl)C1-C6 Alkyl-, R ^y is hydrogen, R ^b is hetAr ¹ , Ar ¹ , hetCyc ¹ or Cyc ¹ , wherein hetAr ¹ and Ar ¹ are as defined for formula I, hetCyc ¹ is as defined for formula I, with the proviso that hetCyc ¹ is a partially unsaturated heterocyclic ring, and Cyc ¹ is as defined for formula I, with the proviso that Cyc ¹ is a partially unsaturated C3-C6 cycloalkyl ring, and ^Ra is as defined for formula I; or

(f) For compounds of formula I satisfying the following conditions: wherein R ^y is hydrogen, R ² is C1-C6 alkyl, fluoro C1-C6 alkyl, cyano C1-C6 alkyl, hydroxyl C1-C6 alkyl, C3 -C6 cycloalkyl or (C3-C6 cycloalkyl) C1-C6 alkyl- and R ¹ is

wherein R ^b is hydrogen, and R ^a is as defined for formula I, such that a compound of formula

wherein ^Ry is hydrogen, ^Rb is hydrogen and ^Ra is as defined for formula I, reacted with a reagent of formula ^R2 -X, wherein ^R2 is C1-C6 alkyl, fluoroC1-C6 alkyl, cyano C1-C6 alkyl, hydroxyC1-C6 alkyl, C3-C6 cycloalkyl or (C3-C6 cycloalkyl)C1-C6 alkyl- and X is halogen; or

(g) For compounds of formula I where ^R is hydrogen, ^R is as defined for formula I and ^R is

wherein R ^b is hydrogen, and R ^a is as defined for formula I, such that a compound of formula

wherein R ^y is hydrogen and R ² is as defined for formula I, reacted with a reagent of formula R ^b C≡CR ^a , wherein R ^b is hydrogen and R ^a is as defined for formula I; or

(h) For compounds of formula I where ^R is hydrogen ^and R and ^R are as defined for formula I, such that a compound of formula

wherein ^Ry is hydrogen and ^R2 is as defined for formula I, reacted with a reagent having the formula

wherein ^R is as defined for formula I; or

(i) For compounds of formula I where ^R is an unsubstituted triazolyl ring, ^R is hydrogen and ^R is as defined for formula I, such that a compound of formula

react with azidotrimethylsilane; or

(j) For compounds of formula I satisfying the following conditions: wherein ^R is a triazolyl ring substituted by C1-C6 alkyl or C3-C6 cycloalkyl, ^Ry is hydrogen and ^R2 is as defined for formula I, make a compound of the formula

wherein ^R is hydrogen and ^R is as defined for formula I, reacted with a reagent of formula R ^-X , wherein ^R is C1-C6 alkyl or C3-C6 cycloalkyl and X is halogen; or

(k) For compounds of formula I satisfying the following conditions: wherein R ^y is HC(=O)-, R ^b is hydrogen, R ² is as defined for formula I, R ¹ is

wherein R ^b is hydrogen and R ^a is as defined for formula I, such that a compound of formula

wherein R is ^{hydrogen and} R and ^R are as defined for formula I, reacted with ammonium hydroxide; or

(l) For compounds of formula I satisfying the following conditions: wherein R ^y is HOCH ₂ -, R ^b is hydrogen, R ² is as defined for formula I, and R ¹ is

wherein R ^b is hydrogen and R ^a is as defined for formula I, such that a compound of formula

wherein R is ^{hydrogen and} R and ^R are as defined for formula I, reacted with an aldehyde reducing agent; and

Any protecting groups are removed, and pharmaceutically acceptable salts thereof are formed as appropriate.

The ability of test compounds to act as RET inhibitors can be demonstrated by the assays described in Examples AC. _IC50 values are shown in Table 5 .

In some embodiments, compounds provided herein exhibit potent and selective RET inhibition. For example, the compounds provided herein exhibit nanomolar potency against wild-type RET and the RET kinase encoded by the RET gene including activating mutations or RET kinase inhibitor resistance mutations including, for example, KIF5B-RET fusions, G810R and G810S ATP cleft-front mutations, M918T activating mutations, and V804M, V804L, and V804E gatekeeper mutations, and minimal activity against associated kinases.

In some embodiments, the compounds provided herein exhibit targeting of a RET fusion protein encoded by a RET fusion protein, such as any of the RET fusion proteins described herein, including but not limited to CCDC6-RET or KIF5B-RET. Nanomolar concentration potency of variant RET fusion proteins encoded by genes comprising RET kinase inhibitor resistance mutations (such as any of the RET mutations described herein, including but not limited to, V804M, V804L, or V804E), so that the variant RET protein is a RET fusion protein that exhibits RET kinase resistance due to the presence of RET kinase inhibitor resistance amino acid substitutions or deletions. Non-limiting examples include CCDC6-RET-V804M and KIF5B-RET-V804M. In some embodiments, the compounds provided herein exhibit nanomolar potency against a variant RET protein encoded by a RET gene comprising a RET mutation (such as any of the RET mutations described herein, including (but not limited to, C634W or M918T) and includes a RET kinase inhibitor resistance mutation (such as any of the RET kinase inhibitor resistance mutations described herein, including but not limited to, V804M, V804L, or V804E) , so that the variant RET protein includes RET substitutions caused by RET mutations (eg, RET initial mutations) and the variant RET protein exhibits RET kinase resistance due to the presence of RET kinase inhibitor-resistant amino acid substitutions or deletions.

In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, selectively targets RET kinase. For example, a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, may selectively target RET kinase relative to another kinase or a non-kinase target.

In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, exhibits at least 30-fold selectivity for RET kinase relative to another kinase. For example, relative to another kinase, the compound of formula I or a pharmaceutically acceptable salt or solvate thereof exhibits at least 40-fold selectivity for RET kinase; at least 50-fold selectivity; at least 60-fold selectivity; at least 70-fold selectivity At least 80-fold selectivity; At least 90-fold selectivity; At least 100-fold selectivity; At least 200-fold selectivity; At least 300-fold selectivity; At least 400-fold selectivity; At least 500-fold selectivity; At least 600-fold selectivity at least 700-fold selectivity; at least 800-fold selectivity; at least 900-fold selectivity; or at least 1000-fold selectivity. In some embodiments, selectivity for a RET kinase is measured relative to another kinase in a cellular assay, such as the cellular assays provided herein.

In some embodiments, the compounds provided herein can exhibit selectivity for a RET kinase (eg, VEGFR2) relative to a KDR kinase. In some embodiments, selectivity for RET kinase over KDR kinase was observed without loss of potency for RET kinase encoded by the RET gene including activating mutations or RET kinase inhibitor resistance mutations (eg, gatekeeper mutants). In some embodiments, the selectivity is at least 10-fold over KDR kinase (e.g., at least 40-fold selectivity; at least 50-fold selectivity; at least 60-fold selectivity; at least 70-fold selectivity; at least 70-fold selectivity) compared to inhibition of KIF5B-RET 80-fold selectivity; at least 90-fold selectivity; at least 100-fold selectivity; at least 150-fold selectivity; at least 200-fold selectivity; at least 250-fold selectivity; at least 300-fold selectivity; at least 350-fold selectivity; or at least 400-fold fold selectivity) (eg, compounds are more potent for KIF5B-RET than KDR). In some embodiments, the selectivity for RET kinase is about 30-fold over KDR kinase. In some embodiments, the selectivity for RET kinase is at least 100-fold over KDR kinase. In some embodiments, the selectivity for RET kinase is at least 150-fold over KDR kinase. In some embodiments, the selectivity for RET kinase is at least 400-fold over KDR kinase. Without being bound by any theory, it is believed that potent KDR kinase inhibition is a common feature among multiple kinase inhibitors (MKIs) targeting RET and may be the source of the dose-limiting toxicity observed with such compounds.

In some embodiments, the inhibition by V804M is similar to that observed for wild-type RET. For example, the inhibition of V804M is within about 2-fold (eg, about 5-fold, about 7-fold, about 10-fold) that of wild-type RET (ie, the compounds are similarly potent against wild-type RET and V804M). In some embodiments, selectivity for a wild-type or V804M RET kinase over another kinase is measured in an enzyme assay, such as an enzyme assay provided herein. In some embodiments, the compounds provided herein exhibit selective cytotoxicity against RET mutant cells.

In some embodiments, the inhibition of G810S and/or G810R is similar to that observed for wild-type RET. For example, the inhibition of G810S and/or G810R is within about 2-fold (e.g., about 5-fold, about 7-fold, about 10-fold) of the inhibition of wild-type RET (e.g., compounds against wild-type RET and G810S and/or G810R performance is similar). In some embodiments, selectivity for wild-type or G810S and/or G810R RET kinase over another kinase is measured in an enzyme assay, such as an enzyme assay provided herein. In some embodiments, the compounds provided herein exhibit selective cytotoxicity against RET mutant cells.

In some embodiments, compounds provided herein exhibit brain and/or central nervous system (CNS) permeability. Such compounds are able to cross the blood-brain barrier and inhibit RET kinase in the brain and/or other CNS structures. In some embodiments, compounds provided herein are capable of crossing the blood-brain barrier in therapeutically effective amounts. For example, treatment of a patient with cancer (eg, a RET-associated cancer, such as a RET-associated brain or CNS cancer) can include administering (eg, oral administration) a compound to the patient. In some such embodiments, the compounds provided herein are useful in the treatment of primary brain tumors or metastatic brain tumors. For example, RET-associated primary brain tumors or metastatic brain tumors.

In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, exhibits one or more of high GI absorption, low clearance, and low potential for drug-drug interactions.

Compounds of formula I or pharmaceutically acceptable salts or solvates thereof are useful in the treatment of diseases and conditions treatable with RET kinase inhibitors, such as RET-associated diseases and conditions, such as proliferative disorders, such as cancers, including hematological cancers and entities Tumors (eg, advanced solid tumors and/or RET fusion-positive solid tumors), and gastrointestinal disorders, such as IBS.

As used herein, the term "treat" or "treatment" refers to curative or palliative measures. Beneficial or desired clinical outcomes include, but are not limited to, complete or partial remission of symptoms associated with a disease or disorder or condition, reduction in extent of disease, stabilization of disease status (i.e., not worsening), delay or slowing of disease progression, disease Improvement or alleviation of a condition, such as one or more symptoms of a disease, and remission, whether partial or total, whether detectable or not. "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment.

As used herein, the terms "subject", "individual" or "patient" are used interchangeably to refer to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, Cats, pigs, cattle, sheep, horses, primates and humans. In some embodiments, the patient is human. In some embodiments, the individual has experienced and/or exhibited at least one symptom of the disease or condition being treated and/or prevented. In some embodiments, the individual has been identified or diagnosed as having a cancer with dysregulation of the expression or activity or level of the RET gene, RET protein, or either (RET-associated cancer) (e.g., using a regulatory agency-approved (e.g., FDA-approved) analytical method or set of assays). In some embodiments, the individual has a tumor that is positive for RET gene, RET protein, or dysregulation of the expression or activity or level of either (eg, as determined using a regulatory agency approved assay or panel). An individual can be an individual with a tumor positive for RET gene, RET protein, or dysregulation of the expression or activity or level of either (e.g., identified as positive using a regulatory agency-approved (e.g., FDA-approved) assay or kit. ). An individual can be one whose tumor has a dysregulation of the RET gene, RET protein, or expression or activity or level thereof (eg, using a regulatory agency-approved (eg, FDA-approved) assay or panel to identify a tumor as having such a dysregulation). In some embodiments, the individual is suspected of having a RET-associated cancer. In some embodiments, the individual's clinical records indicate that the individual has a tumor that has a dysregulation of the expression or activity or amount of the RET gene, RET protein, or either (and optionally, the individual's clinical records indicate that the individual uses the any one of the compositions in the treatment). In some embodiments, the patient is a pediatric patient.

As used herein, the term "pediatric patient" refers to a patient who is younger than 21 years of age at the time of diagnosis or treatment. The term "pediatrics" can be further divided into subgroups, including: neonates (birth to first month of life); infants (one month to two years); children (two years to 12 years); and adolescents (12 years to the age of 21 (up to but not including the twenty-second birthday)). Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics , 15th ed. Philadelphia: WB Saunders Company, 1996; Rudolph AM et al., Rudolph 's Pediatrics , 21st ed. New York: McGraw-Hill, 2002; and Avery MD, First LR. Pediatric Medicine , 2nd ed. Baltimore: Williams &Wilkins; 1994. In some embodiments, the pediatric patient is from birth to first 28 days of life, 29 days to less than two years of age, two years to less than 12 years of age, or 12 years to 21 years of age (up to but not including the twenty-second birthday) . In some embodiments, the pediatric patient is from birth to first 28 days of life, 29 days to less than 1 year, one month to less than four months, three months to less than seven months, six months to less than one year , 1 year old to less than 2 years old, 2 years old to less than 3 years old, 2 years old to less than 7 years old, 3 years old to less than 5 years old, 5 years old to less than 10 years old, 6 years old to less than 13 years old, 10 years old to less than 15 years old, Or 15 years old to less than 22 years old.

In certain embodiments, compounds of formula I, or pharmaceutically acceptable salts or solvates thereof, are useful in the prevention of diseases and disorders as defined herein (eg autoimmune diseases, inflammatory diseases and cancer). As used herein, the term "prevention" means preventing the disease or condition as described herein, in whole or in part, from the onset, recurrence or spread of symptoms thereof.

As used herein, the term "RET-associated disease or disorder" refers to a disorder related to the expression or activity or level of the RET gene, RET kinase (also referred to herein as RET kinase protein), or any one (e.g., one or more) thereof (such as any type of disorder in the expression or activity or content of the RET gene, RET kinase, RET kinase domain, or any of those described herein) is associated with or has such a disorder or disorder. Non-limiting examples of RET-associated diseases or disorders include, for example, cancer and gastrointestinal disorders such as irritable bowel syndrome (IBS).

As used herein, the term "RET-associated cancer" refers to a cancer associated with or having a dysregulation of the RET gene, RET kinase (also referred to herein as RET kinase protein), or the expression or activity or level of either. Non-limiting examples of RET-associated cancers are described herein.

The phrase "disregulation of the expression or activity or content of the RET gene, RET kinase, or any of them" refers to a genetic mutation (such as a chromosomal translocation that causes expression of a fusion protein comprising the RET kinase domain and a fusion partner, causing RET gene mutations causing expression of RET protein with one amino acid deletion (compared to wild-type RET protein), RET gene mutations causing expression of RET protein with one or more point mutations (compared to wild-type RET protein) , a mutation in the RET gene that causes expression of a RET protein with at least one inserted amino acid (compared to a wild-type RET protein), a gene duplication that causes an increase in the amount of the RET protein in a cell, or an increase in the amount of the RET protein in a cell regulatory sequences (such as promoters and/or enhancers) mutations), alternative spliced forms of RET mRNA that produce RET proteins that have at least one amino acid deletion in the RET protein (compared to wild-type RET protein), or due to Enhanced expression (eg, increased level) of wild-type RET kinase in mammalian cells (eg, compared to control non-cancerous cells) resulting from abnormal cell signaling and/or dysregulation of autocrine/paracrine signaling. As another example, a dysregulation of the expression or activity or level of the RET gene, the RET protein, or any of them may be a mutation in the RET gene encoding a RET protein that is constitutively active or compared to the The protein encoded by the RET gene has increased activity. For example, dysregulation of the expression or activity or level of the RET gene, RET protein, or either may be the result of a gene or chromosomal translocation that results in a first portion of RET that includes a functional kinase domain Expression of the fusion protein with the second part of the partner protein (ie, not RET). In some instances, dysregulation of the expression or activity or level of a RET gene, RET protein, or either may be the result of a genetic translocation of one RET gene with another non-RET gene. Non-limiting examples of fusion proteins are described in Table 1. Non-limiting examples of RET kinase protein point mutations/insertions/deletions are described in Table 2. Other examples of RET kinase protein mutations (eg, point mutations) are RET inhibitor resistance mutations. Non-limiting examples of RET inhibitor resistance mutations are described in Tables 3 and 4.

In some embodiments, dysregulation of the expression or activity or level of the RET gene, RET kinase, or either can be caused by an activating mutation of the RET gene (see, e.g., chromosomal translocations that cause expression of any of the fusion proteins listed in Table 1 ). In some embodiments, dysregulation of the expression or activity or level of the RET gene, RET kinase, or either may result from a genetic mutation that results in inhibition of a RET kinase inhibitor and/or multiple kinase inhibitor (MKI) Expression of RET kinase with increased resistance, eg compared to wild-type RET kinase (see eg amino acid substitutions in Tables 3 and 4). In some embodiments, dysregulation of the expression or activity or level of the RET gene, RET kinase, or any of them can be caused by a nucleic acid encoding a variant RET protein (e.g., a RET fusion protein or a RET protein with a mutation (e.g., an initial mutation)). Caused by mutations that cause the expression of a variant RET protein with increased resistance to inhibition by RET kinase inhibitors and/or multiple kinase inhibitors (MKI), e.g. compared to wild-type RET kinase (see e.g. Table 3 and Amino acid substitution in 4). Exemplary RET kinase point mutations, insertions and deletions shown in Table 2 may result from activating mutations and/or may result in RET with increased resistance to inhibition by RET kinase inhibitors and/or multiple kinase inhibitors (MKIs) Kinase expression.

The term "activating mutation" describes a mutation in the RET kinase gene which results in the expression of RET kinase with increased kinase activity, eg compared to wild-type RET kinase, eg when assayed under the same conditions. For example, activating mutations can result in the expression of a fusion protein comprising the RET kinase domain and the fusion partner. In another example, the activating mutation can be a mutation in the RET kinase gene that results in one or more (e.g., two, three, four, five, six, seven, eight, nine, or ten) a) expression of an amino acid substituted RET kinase (e.g. any combination of any of the amino acid substitutions described herein), which RET kinase has increased kinase activity, e.g. compared to wild-type RET kinase, e.g. under the same conditions When analyzing. In another example, the activating mutation can be a mutation in the RET kinase gene that results in one or more (e.g., two, three, four, five, six, seven, eight, nine, or ten) a) The performance of the amino acid deleted RET kinase, eg compared to wild-type RET kinase, eg when assayed under the same conditions. In another example, the activating mutation can be a mutation in the RET kinase gene that results in at least one (e.g., at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8 , at least 9, at least 10, at least 12, at least 14, at least 16, at least 18 or at least 20) RET kinase expression of inserted amino acids, e.g. compared to wild-type RET kinase, e.g. Exemplary wild-type RET kinase described herein, for example, when assayed under the same conditions. Other examples of activating mutations are known in the art.

The term "wildtype/wild-type" describes a nucleic acid (e.g. RET gene or RET mRNA, EGFR gene or EGFR mRNA, MET gene or MET mRNA, MDM2 gene or MDM2 mRNA) or protein (eg RET protein, EGFR protein, MET protein, MDM2 protein).

The term "wildtype RET (wildtype RET/wild-type RET)" describes a RET nucleic acid (such as RET gene or RET mRNA) or RET protein, which is found in people who do not have a RET-related disease (such as RET-related cancer) (and optionally also do not have an increased risk of developing a RET-associated disease and/or are not suspected of having a RET-associated disease), or are found in individuals who do not have a RET-associated disease (such as a RET-associated cancer) (and, as the case may be, do not have an increased in cells or tissues of individuals who are at risk of developing a RET-associated disease and/or are not suspected of having a RET-associated disease.

The term "regulatory agency" means a national agency that authorizes the medical use of a medicinal product. By way of example, a non-limiting example of a regulatory agency is the U.S. Food and Drug Administration (FDA).

The present invention provides a method of treating cancer (e.g., RET-associated cancer) in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof or its pharmaceutical composition. For example, provided herein is a method of treating RET-associated cancer in a patient in need of such treatment, the method comprising a) detecting the expression or activity or amount of the RET gene, RET kinase, or either, in a sample from the patient and b) administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the dysregulation of the expression or activity or level of the RET gene, RET kinase, or either comprises one or more fusion proteins. Non-limiting examples of RET gene fusion proteins are described in Table 1. In some embodiments, the fusion protein is KIF5B-RET. In some embodiments, the dysregulation of the expression or activity or level of RET gene, RET kinase, or any of them comprises one or more point mutations/insertions of RET kinase proteins. Non-limiting examples of RET kinase protein point mutations/insertions/deletions are described in Table 2. In some embodiments, the RET kinase protein point mutation/insertion/deletion is selected from the group consisting of M918T, M918V, C634W, V804L, V804M, G810S, and G810R. In some embodiments, the RET kinase protein point mutation/insertion/deletion occurs in a RET fusion protein (eg, any of the RET gene fusion proteins described in Table 1). In some embodiments, the compound of Formula I is selected from Examples 1-34 or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula I is selected from the compounds of Examples 1-10, Examples 11-20, Examples 21-34, or pharmaceutically acceptable salts or solvates thereof.

In some embodiments of any of the methods or uses described herein, the cancer (eg, RET-related cancer) is a hematological cancer. In some embodiments of any of the methods or uses described herein, the cancer (eg, a RET-associated cancer) is a solid tumor (eg, an advanced solid tumor and/or a RET fusion-positive solid tumor). In some embodiments of any of the methods or uses described herein, the cancer (e.g., a RET-related cancer) is lung cancer (e.g., small cell lung cancer or non-small cell lung cancer), thyroid cancer (e.g., papillary thyroid cancer, Medullary thyroid cancer (eg, sporadic or hereditary medullary thyroid cancer), differentiated thyroid cancer, recurrent thyroid cancer, or refractory differentiated thyroid cancer), thyroid carcinoma, endocrine gland neoplasm, lung adenocarcinoma , bronchiopulmonary cell carcinoma, type 2A or 2B multiple endocrine neoplasia (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, breast cancer, breast carcinoma, breast tumor, colorectal cancer (eg metastatic colorectal cancer), papillary renal cell carcinoma, gangliomatosis of the gastrointestinal mucosa, inflammatory myofibroblastic tumor, or cervical cancer. In some embodiments of any of the methods or uses described herein, the cancer (e.g., RET-associated cancer) is selected from the group consisting of acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML) , juvenile cancer, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytoma, atypical teratoid/rhabdoid tumor, basal cell carcinoma, cholangiocarcinoma, bladder cancer, bone cancer, brainstem glioma, brain tumor , breast cancer, bronchial neoplasms, Burkitt lymphoma, carcinoid, unknown primary carcinoma, cardiac tumors, cervical cancer, childhood cancer, chordoma, chronic lymphocytic leukemia (CLL), chronic myeloid Leukemia (CML), chronic myeloproliferative neoplasm, focal neoplasm, neoplasm, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, cutaneous angiosarcoma, cholangiocarcinoma, breast ductal carcinoma in situ , embryonal tumors, endometrial cancer, ependymoma, esophageal cancer, sensitive neuroblastoma, Ewing sarcoma, extracranial germ cell tumors, extragonadal germ cell tumors, extrahepatic cholangiocarcinoma, ocular Carcinoma, fallopian tube cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, gastrointestinal carcinoid, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic disease, glioma, hairy cell tumor, hairy cell tumor Cellular leukemia, head and neck cancer, breast neoplasm, head and neck neoplasm, CNS tumor, primary CNS tumor, cardiac cancer, hepatocellular carcinoma, histiocytosis, Hodgkin's lymphoma, Hypopharyngeal cancer, intraocular melanoma, islet cell tumor, pancreatic neuroendocrine tumor, Kaposi sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia , lip and mouth cancer, liver cancer, lung cancer, lymphoma, macroglobulinemia, malignant fibrous histiocytoma of bone, osteosarcoma, melanoma, Merkel cell carcinoma, mesothelioma, metastatic Squamous neck cancer, midline cancer, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma, mycosis fungoides, myelodysplastic syndrome, myelodysplasia/myeloproliferative neoplasia, localized neoplasia, neoplasia, Myeloid leukemia, myeloid leukemia, multiple myeloma, myeloproliferative neoplasm, nasal cavity and sinus cancer, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer , lung cancer, lung cancer, lung neoplasm, respiratory tract neoplasm, bronchial carcinoma, bronchial neoplasm, oral cancer, oral cavity cancer, lip cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papilloma, Paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharynx cancer, pheochromocytoma, pituitary cancer, plasma cell tumor, pleuropulmonary blastoma, pregnancy-related breast cancer, primary central nervous system Lymphoma, primary peritoneal cancer, prostate cancer, rectal cancer, colon cancer, colonic neoplasia, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Sezary syndrome, skin cancer , Spitz tumors, small cell lung cancer, small bowel cancer, soft tissue sarcoma, squamous cell carcinoma, squamous neck cancer, gastric cancer, T cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid Carcinoma, transitional cell carcinoma of the renal pelvis and urinary tract, unknown primary carcinoma, urethral carcinoma, uterine carcinoma, uterine sarcoma, vaginal carcinoma, vulvar carcinoma, and Wilms' tumor.

In some embodiments, the blood cancer (eg, a blood cancer that is a RET-associated cancer) is selected from the group consisting of leukemia, lymphoma (non-Hodgkin's lymphoma), Hodgkin's disease (also known as Hodgkin's disease) Acute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML), Acute Promyelocytic Leukemia (APL), Chronic Lymphocytic Leukemia (CLL), Chronic Myeloid Leukemia Leukemia (CML), chronic myelomonocytic leukemia (CMML), chronic neutrophilic leukemia (CNL), acute undifferentiated leukemia (AUL), pleomorphic large cell lymphoma (ALCL), prolymphocytic Leukemia (PML), juvenile myelomonocytic leukemia (JMML), adult T-cell ALL, AML with trilineage myelodysplasia (AML/TMDS), mixed lineage leukemia (MLL), myelodysplastic syndrome (MDS), Myeloproliferative disease (MPD) and multiple myeloma (MM). Other examples of hematological cancers include myeloproliferative disorders (MPDs), such as polycythemia vera (PV), essential thrombocytopenia (ET), and idiopathic primary myelofibrosis (IMF/IPF/PMF). In some embodiments, the hematological cancer (eg, a hematological cancer that is a RET-associated cancer) is AML or CMML.

In some embodiments, the cancer (eg, RET-associated cancer) is a solid tumor. Examples of solid tumors (e.g., as RET-associated cancers) include, e.g., thyroid cancer (e.g., papillary thyroid cancer, medullary thyroid cancer), lung cancer (e.g., lung adenocarcinoma, small cell lung cancer), pancreatic cancer, pancreatic ductal cancer , breast cancer, colon cancer, colorectal cancer, prostate cancer, renal cell carcinoma, head and neck cancer, neuroblastoma and melanoma. See eg Nature Reviews Cancer, 2014, 14, 173-186.

In some embodiments, the cancer line is selected from the group consisting of lung cancer, papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, refractory differentiated thyroid cancer, multiple endocrine neoplasia type 2A or 2B (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, gangliomatosis of the gastrointestinal mucosa, and cervical cancer.

In some embodiments, the patient is human.

Compounds of formula I and their pharmaceutically acceptable salts and solvates are also suitable for the treatment of RET-associated cancers.

Accordingly, also provided herein are methods for treating a patient diagnosed or identified as having a RET-associated cancer, such as any of the exemplary RET-associated cancers disclosed herein, comprising administering to the patient a therapeutically effective amount of, for example, A compound of formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof. In some embodiments, the compound of Formula I is selected from Examples 1-34 or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula I is selected from the compounds of Examples 1-10, Examples 11-20, Examples 21-34, or pharmaceutically acceptable salts or solvates thereof.

Dysregulation of the expression or activity or level of RET kinase, RET gene, or any one (eg, one or more) of them can promote tumor formation. For example, a dysregulation of the expression or activity or level of RET kinase, RET gene, or any of them may be a translocation, overexpression, activation, amplification, or mutation of RET kinase, RET gene, or RET kinase domain. Translocations can include genetic translocations that result in the expression of a fusion protein comprising a RET kinase domain and a fusion partner. For example, a fusion protein can have increased kinase activity compared to wild-type RET protein. In some embodiments, mutations in the RET gene may involve mutations in the RET ligand binding site, ectodomain, kinase domain, and regions involved in protein:protein interactions and downstream signaling. In some embodiments, a mutation (eg, an activating mutation) in the RET gene results in the expression of a RET kinase having one or more (eg, two, three, four, five, six, seven) , eight, nine or ten) amino acid substitutions (e.g., kinase domain (e.g., amino acid positions 723 to 1012 in wild-type RET protein), gatekeeper amino acids (e.g., amino acids in wild-type RET protein position 804), P loop (e.g. amino acid positions 730-737 in wild-type RET protein), DFG motif (e.g. amino acid positions 892-894 in wild-type RET protein), ATP cleft solvent front amine group acid (such as amino acid positions 758, 811, and 892 in the wild-type RET protein), the activation loop (such as amino acid positions 891-916 in the wild-type RET protein), the C-helix, and the loop before the C-helix (such as the wild-type RET protein amino acid position 768-788 in the wild-type RET protein), and/or the ATP binding site (for example, amino acid position 730-733, 738, 756, 758, 804, 805, 807, 811 in the wild-type RET protein , 881 and 892) one or more amino acid substitutions). In some embodiments, the mutation is a gene amplification of the RET gene. In some embodiments, a mutation in the RET gene (e.g., an activating mutation) results in the expression of a RET kinase or RET receptor that does not have at least one amino acid compared to the wild-type RET protein (e.g., At least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 12, at least 14, at least 16, at least 18 , at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, or at least 50 amino acids). In some embodiments, the dysregulation of RET kinase may be increased expression (e.g., increased levels) of wild-type RET kinase in mammalian cells due to abnormal cell signaling and/or dysregulation of autocrine/paracrine signaling ( e.g. compared to control non-cancerous cells). In some embodiments, a mutation in the RET gene (e.g., an activating mutation) results in the expression of a RET kinase or RET receptor having at least one inserted amino acid compared to the wild-type RET protein (e.g., At least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 12, at least 14, at least 16, at least 18 , at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, or at least 50 amino acids). In some embodiments, the dysregulation of RET kinase may be increased expression (e.g., increased levels) of wild-type RET kinase in mammalian cells due to abnormal cell signaling and/or dysregulation of autocrine/paracrine signaling ( e.g. compared to control non-cancerous cells). Other disorders may include RET mRNA splice variants. In some embodiments, the wild-type RET protein is an exemplary wild-type RET protein described herein.

In some embodiments, dysregulation of the expression or activity or level of the RET gene, RET kinase, or either comprises overexpression of wild-type RET kinase (eg, causing autocrine activation). In some embodiments, dysregulation of the expression or activity or level of the RET gene, the RET kinase protein, or either comprises overexpression, activation, amplification, or mutation in the chromosomal segment comprising the RET gene or its A portion includes, for example, a portion of a kinase domain, or a portion capable of exhibiting kinase activity.

In some embodiments, the RET gene, the RET kinase protein, or the expression or activity or level of any one of the dysregulation includes one or more chromosomal translocations or inversions, thereby causing RET gene fusion. In some embodiments, the dysregulation of the expression or activity or level of the RET gene, the RET kinase protein, or either is the result of a genetic translocation wherein the expressed protein is a fusion comprising residues from a non-RET partner protein protein and includes a minimal functional RET kinase domain.

¹ Grubbs et al.,J. Clin. Endocrinol. Metab. 100:788-793, 2015.² Halkova et al.,Human Pathology 46:1962-1969, 2015.³ U.S. Patent No. 9,297,011⁴ U.S. Patent No. 9,216,172⁵ Le Rolle et al.,Oncotarget . 6(30):28929-37, 2015.⁶ Antonescu et al.,Am J Surg Pathol. 39(7):957-67, 2015.⁷ U.S. Patent Application Publication No. 2015/0177246.⁸ U.S. Patent Application Publication No. 2015/0057335.⁹ Japanese Patent Application Publication No. 2015/109806A.¹⁰ Chinese Patent Application Publication No. 105255927A.¹¹ Fang, et al.Journal of Thoracic Oncology 11.2 (2016): S21-S22.¹² European Patent Application Publication No. EP3037547A1.¹³ Lee et al.,Oncotarget . DOI: 10.18632/oncotarget.9137, e-published ahead of printing, 2016.¹⁴ Saito et al.,Cancer Science 107:713-720, 2016.¹⁵ Pirker et al.,Transl. 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Aug 8 (2016): 7.²⁷ Sabari et al.,Oncoscience , Advance Publications,www.impactjournals.com/oncoscience/files/papers/1/345/345.pdf, 2017.²⁸ U.S. Patent Application Publication No. 2017/0014413.²⁹ Lu et al., Oncotarget, 8(28):45784-45792, doi: 10.18632/oncotarget.17412, 2017.³⁰ Hirshfield et al.,Cancer Research , (February 2017) Vol. 77, No. 4, Supp. 1. Abstract Number: P3-07-02. Meeting Info: 39th Annual CTRC-AACR San Antonio Breast Cancer Symposium. San Antonio, TX, United States. 06 Dec 2016-10 Dec 2016.³¹ Morgensztern et al.,Journal of Thoracic Oncology , (January 2017) Vol. 12, No. 1, Supp. 1, pp. S717-S718, Abstract Number: P1.07-035, Meeting Info: 17th World Conference of the International Association for the Study of Lung Cancer, IASLC 2016. Vienna, Austria. 04 Dec 2016.³² Dogan et al.,Laboratory Investigation , (February 2017) Vol. 97, Supp. 1, pp. 323A. Abstract Number: 1298, Meeting Info: 106th Annual Meeting of the United States and Canadian Academy of Pathology, USCAP 2017. San Antonio, TX, United States.³³ Dogan et al., MODERN PATHOLOGY, Vol. 30, Supp. [2], pp. 323A-323A. MA 1298, 2017.³⁴ PCT Patent Application Publication No. WO 2017/146116.³⁵ PCT Patent Application Publication No. WO 2017/122815.³⁶ Reeser et al.,J. Mol. Diagn. , 19(5):682-696, doi: 10.1016/j.jmoldx.2017.05.006, 2017.³⁷ Ibrahimpasic et al.,Clin. Cancer Res. , doi: 10.1158/1078-0432.CCR-17-1183, 2017.³⁸ Kloosterman et al.,Cancer Res. , 77(14):3814-3822. doi: 10.1158/0008-5472.CAN-16-3563, 2017.³⁹ Chai et al.,Oncology Reports, 35 (2): 962-970. doi: 10.3892/or.2015.4466, 2015.⁴⁰ Gautschi et al.Journal of Clinical Oncology , 35(13) 1403-1410. doi: 10.1200/JCO.2016.70.9352, 2017.⁴¹ Lee et al.Annals of Oncology , 28(2), 292-297. doi: 10.1093/annonc/mdw559, 2016.⁴² Zheng et al.Nature Medicine , 20(12), 1479-1484. doi: 10.1038/nm.3729, 2014.⁴³ Zhang et al.Lung Cancer , 118, 27-29. doi: 10.1016/j.lungcan.2017.08.019, 2018.⁴⁴ Morano et al.Molecular Cancer Therapeutics , (January 2018) Vol. 17, No. 1, Supp. Supplement 1. Abstract Number: B049. Meeting Info: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics 2017.⁴⁵ Wang et al.Journal of Thoracic Oncology , (November 2017) Vol. 12, No. 11, Supp. Supplement 2, pp. S2105. Abstract Number: P2.02-018. Meeting Info: 18th World Conference on Lung Cancer of the International Association for the Study of Lung Cancer, IASLC 2017. Yokohama, Japan. 15 Oct 2017-18 Oct 2017.⁴⁶ Gao et al.Cell Reports , 23(1), 227-238. doi: 10.1016/j.celrep.2018.03.050, 2018.⁴⁷ U.S. Patent Application Publication No. 2016/0010068.⁴⁸ VandenBoom, et al.Am. J. Surg. Pathol. 42(8): 1042-1051, 2018. doi: 10.1097/PAS.0000000000001074⁴⁹ Cao, et al.Onco. Targets. Ther. 2018(11):2637-2646, 2018. doi: 10.2147/OTT.S155995⁵⁰ Luo, et al.Int. J. Cancer , 2018. epub ahead of print. doi: 10.1002/ijc.31542⁵¹ Guilmette, et al.Hum Pathol. pii: S0046-8177(18)30316-2, 2018. doi: 10.1016/j.humpath.2018.08.011⁵² Zhao, et al.Journal of Clinical Oncology Vol 36, No. 15, Supp. [S], MA e21139.⁵³ Paratala, et al.Nat. Comm . 2018 Nov 16;9(1):4821. doi: 10.1038/s41467-018-07341-4.⁵⁴ Al-Ibraheemi, et al.Mod Pathol . 2018 Oct 11. doi: 10.1038/s41379-018-0150-3⁵⁵ Fei, et al.Journal of Thoracic Oncology , (December 2018) Vol. 13, No. 12, Supp. Supplement, pp. S1077. Meeting Info: IASLC Asia Conference on Lung Cancer 2018. Guangzhou, China. 07 Nov 2018-10 Nov 2018. doi: 10.1016/j.jtho.2018.10.094Non-limiting examples of RET fusion proteins are shown in Table 1 . Table 1. Exemplary RET fusion partners and cancers

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In some embodiments, the dysregulation of the expression or activity or level of the RET gene, the RET kinase, or any of them comprises one or more deletions (e.g., deletion of an amino acid at position 4), insertions, or points in the RET kinase. mutation. In some embodiments, dysregulation of the expression or activity or level of the RET gene, RET kinase, or either comprises deletion of one or more residues from the RET kinase, thereby resulting in constitutive activity of the RET kinase domain.

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M,Nature Reviews Cancer , 14(3), 173, 2014, doi: 10.1038/nrc3680⁵⁶ Arighi, et al,Cytokine & Growth Factor Reviews , 16(4-5), 441-467, 2005. doi: 10.1016/j.cytogfr.2005.05.010⁵⁷ Dabir, et al,Journal of Thoracic Oncology , 9(9), 1316-1323, 2014. doi: 10.1097/JTO.0000000000000234⁵⁸ Uchino, et al,Cancer Science , 90(11), 1231-1237, 1999. doi: 10.1111/j.1349-7006.1999.tb00701.x⁵⁹ Krampitz.Cancer , 120(13), 1920-1931, 2014: 10.1002/cncr.28661⁶⁰ Jhiang et al, Thyroid 6(2), 1996. doi: 10.1089/thy.1996.6.115⁶¹ Dvořáková, et al,Thyroid , 16(3), 311-316, 2006. doi: 10.1089/thy.2006.16.311⁶² Severskaya et al,Genomics Transcriptomics Proteomics , 40(3) 425-435.⁶³ Elisei, et al,Journal of Genetic Syndromes & Gene Therapy , 5(1), 1, 2014. doi: 10.4172/2157-7412.1000214⁶⁴ Ahmed et al, The Journal of Molecular Diagnostics, 7(2), 283-288, 2005. doi: 10.1016/S1525-1578(10)60556-9⁶⁵ Oliveira, et al.J. Exp. Clin. Cancer Res. 37(84), 2018. doi: 10.1186/s13046-018-0746-y⁶⁶ Yi, et al.Case Rep. Endocrinol . 2018:8657314, 2018. doi: 10.1155/2018/8657914⁶⁷ Huang, et al.Cell . 173(2): 355-370, 2018. doi: 10.1016/j.cell.2018.03.039⁶⁸ Bosic, et al.Pathology . 50(3):327-332, 2018. doi: 10.1016/j.pathol.2017.10.011⁶⁹ Yao, et al.Zhonghua Yi Xue Za Zhi . 87(28):1962-1965, 2007. PMID: 17923033⁷⁰ Quintela-Fandino, et al.Mol. Oncol. 8(8):1719-1728, 2014. doi: 10.1016/j.molonc.2014.07.005⁷¹ Urbini, et al.Int J Genomics 2018: 6582014. doi: 10.1155/2018/6582014⁷² Yu, et al.Clin Lung Cancer , pii: S1525-7304(18)30204-3, 2018. doi: 10.1016/j.cllc.2018.08.010⁷³ Soca-Chafre, et al.Oncotarget 9(55):30499-30512, 2018. doi: 10.18632/oncotarget.25369⁷⁴ Kim, et al.BMC Urol 18(1):68, 2018. doi: 10.1186/s12894-018-0380-1⁷⁵ Qi, et al.PLoS One 6(5):e20353, 2011. doi: 10.1371/journal.pone.0020353⁷⁶ Bartsch, et alExp Clin Endocrinol Diabetes 108(2):128-132, 2000. doi: 10.1055/s-2000-5806⁷⁷ Nunes, et al.J Clin Endocrinol Metab. 87(12):5658-5661, 2002. doi: 10.1210/jc.2002-020345⁷⁸ Plenker et al., Sci. Transl. Med., 9(394), doi: 10.1126/scitranslmed.aah6144, 2017⁷⁹ Romei, et al.,European Thyroid Journal , Vol. 7, Supp. 1, pp 63. Abstract No: P1-07-69. Meeting Info: 41st Annual Meeting of the European Thyroid Association, ETA 2018. 15 Sep 2018-18 Sep 2018. doi: 10.1159/000491542⁸⁰ Ciampi, et al.,European Thyroid Journal , Vol. 7, Supp. 1, pp 63. Abstract No: OP-09-66. Meeting Info: 41st Annual Meeting of the European Thyroid Association, ETA 2018. 15 Sep 2018-18 Sep 2018. doi: 10.1159/000491542⁸¹ Aggarwal, et al.,JAMA Oncol . 2018 Oct 11. doi: 10.1001/jamaoncol.2018.4305.⁸² Pecce, et al.,PLoS Genet . 2018 Oct 15;14(10):e1007678. doi: 10.1371/journal.pgen.1007678. eCollection 2018 Oct.⁸³ Youssef et al.,Anticancer Res . 2018 Oct;38(10):5627-5634. doi: 10.21873/anticanres.12897⁸⁴ Qi, et al. Otolaryngology - Head and Neck Surgery (United States), (October 2018) Vol. 159, No. 1, Supp. Supplement 1, pp. P185. Meeting Info: Annual Meeting of the American Academy of Otolaryngology-Head and Neck Surgery Foundation and OTO Experience, AAO-HNSF 2018. Atlanta, GA, United States. 07 Oct 2018-10 Oct 2018 doi: 10.1177/0194599818787193⁸⁵ U.S. Patent No. 10,119,169⁸⁶ Subbiah, et al.Cancer Discov . 2018 Jul;8(7):836-849. doi: 10.1158/2159-8290.CD-18-0338.In some embodiments, the dysregulation of the expression or activity or level of the RET gene, the RET kinase, or either comprises at least one point mutation in the RET gene that results in the production of a protein having one or more amine groups compared to wild-type RET kinase. RET kinases with acid substitutions, insertions or deletions (see eg point mutations listed in Table 2 ). In some embodiments, the RET gene, RET kinase, or dysregulation of the expression or activity or level of any one of them comprises at least one point mutation in the RET gene, which results in an amino acid substitution, insertion, or deletion having the amino acid substitutions, insertions, or deletions in Table 2 . One or more of the RET kinases. In some embodiments, the dysregulation of the expression or activity or level of the RET gene, RET kinase, or either comprises at least one point mutation in the RET gene that results in RET kinase with a D898-E901 deletion. In some embodiments, the dysregulation of the expression or activity or level of the RET gene, RET kinase, or either comprises at least one point mutation in the RET gene that results in the production of extracellular cysteine (e.g., C618, C620, or RET kinase with a mutation (eg, C618Y, C620R, or C630R) in C630). Table 2. Amino acid substitutions / insertions / deletions in RET kinase proteins ^A

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Endocrine-related cancer 25(4): 421-436. doi: 10.1530/ERC-17-0452, 2018. ⁴⁰ Raue, et al. J. Clin Endocrinol Metab , 103(1): 235-243. doi: 10.1210/jc.2017-01884, 2018. ⁴¹ Nakao, et al. Head and Neck , 35: E363-E368. doi: 10.1002/ hed.23241, 2013. ⁴² Attié, et al. Human Molecular Genetics 4(8): 1381-1386. doi: 10.1093/hmg/4.8.1381, 1995. ⁴³ Fitze, et al. Lancet , 393(9313): 1200 -1205. doi: 10.1016/S0140-6736(02)08218-1, 2002. ⁴⁴ Weng, et al. Zhonghua Nei Ke Za Zhi , 57(2):134-137. doi: 10.3760/cma.j.issn. 0578-1426. 2018.02.010, 2018. ⁴⁵ Chen, et al. Medical Journal of Chinese People's Liberation Army 38.4 (2013): 308-312. ⁴⁶ Gudernova, et al. eLife , 6:e21536. doi: 10.7554 /eLife.21536, 2017. ⁴⁷ Romei, et al. Oncotarget , 9(11): 9875-9884. doi: 10.18632/oncotarget.23986, 2018. ⁴⁸ Plaza-Menacho. Endocr Relat Cancer , 25(2):T79-T90. doi: 10.15 30 /ERC-17-0354, 2017. ⁴⁹ Guerin, et al. Endocr Relat Cancer , 25(2):T15-T28. doi: 10.1530/ERC-17-0266, 2017. ⁵⁰ Roy et al. Oncologist, 18(10 ): 1093-1100. doi: 10.1634/theoncologist.2013-0053, 2013 ⁵¹ US Patent Application Publication No. 2017/0349953 ⁵² Santoro, et al. Endocrinology , 145(12), 5448-5451, 2 004. doi: 10.1210/ EN.2004-0922 ⁵³ US Patent No. 9,006,256 ⁵⁴ Yeganeh, et al. Asian Pac J Cancer Prev , 16 (6), 2107-17. Doi: 10.7314/APJCP.2015.16.2107 ⁵⁵ MULLIGAN, L. M, Nature Reviews Cancer , 14(3), 173, 2014, doi: 10.1038/nrc3680 ⁵⁶ Arighi, et al, Cytokine & Growth Factor Reviews , 16(4-5), 441-467, 2005. doi: 10.1016/j.cytogfr.2005.0 5 .010 ⁵⁷ Dabir, et al, Journal of Thoracic Oncology , 9(9), 1316-1323, 2014. doi: 10.1097/JTO.0000000000000234 ⁵⁸ Uchino, et al, Cancer Science , 90(11), 1231- 1237, 1999 . doi: 10.1111/j.1349-7006.1999.tb00701.x ⁵⁹ Krampitz. Cancer , 120(13), 1920-1931, 2014: 10.1002/cncr.28661 ⁶⁰ Jhiang et al, Thyroid 6(2), 19 96. doi: 10.1089/thy.1996.6.115 ⁶¹ Dvořáková, et al, Thyroid , 16(3), 311-316, 2006. doi: 10.1089/thy.2006.16.311 ⁶² Severskaya et al, Genomics Transcriptomics Proteomics , 4 0(3) 425- 435. ⁶³ Elisei, et al, Journal of Genetic Syndromes & Gene Therapy , 5(1), 1, 2014. doi: 10.4172/2157-7412.1000214 ⁶⁴ Ahmed et al, The Journal of Molecular Diagnostics, 7(2), 283 - 288, 2005. doi: 10.1016/S1525-1578(10)60556-9 ⁶⁵ Oliveira, et al. J. Exp. Clin. Cancer Res. 37(84), 2018. doi: 10.1186/s13046-018-0746-y ⁶⁶ Yi, et al. Case Rep. Endocrinol . 2018:8657314, 2018. doi: 10.1155/2018/8657914 ⁶⁷ Huang, et al. Cell . 173(2): 355-370, 2018. doi: 10.1016/j. cell .2018.03.039 ⁶⁸ Bosic, et al. Pathology . 50(3):327-332, 2018. doi: 10.1016/j.pathol.2017.10.011 ⁶⁹ Yao, et al. Zhonghua Yi Xue Za Zhi . 87(28) :1962-1965, 2007. PMID: 17923033 ⁷⁰ Quintela-Fandino, et al. Mol. Oncol. 8(8):1719-1728, 2014. doi: 10.1016/j.molonc.2014.07.005 ⁷¹ Urbini, et al. Int J Genomics 2018: 6582014. doi: 10.1155/2018/6582014 ⁷² Yu, et al. Clin Lung Cancer , pii: S1525-7304(18)30204-3, 2018. doi: 10.1016/j.cllc.2018. 08.010 ⁷³ Soca-Chafre, et al. Oncotarget 9(55):30499-30512, 2018. doi: 10.18632/oncotarget.25369 ⁷⁴ Kim, et al. BMC Urol 18(1):68, 2018. doi: 10.1186/s12894-01 8 -0380-1 ⁷⁵ Qi, et al. PLoS One 6(5):e20353, 2011. doi: 10.1371/journal.pone.0020353 ⁷⁶ Bartsch, et al Exp Clin Endocrinol Diabetes 108(2):128-132, 2000. doi: 10.1055/s-2000-5806 ⁷⁷ Nunes, et al. J Clin Endocrinol Metab. 87(12):5658-5661, 2002. doi: 10.1210/jc.2002-020345 ⁷⁸ Plenker et al., Sci. Transl. Med., 9(394), doi: 10.1126/scitranslmed.aah6144, 2017 ⁷⁹ Romei, et al., European Thyroid Journal , Vol. 7, Supp. 1, pp 63. Abstract No: P1-07-69. Meeting Info : 41st Annual Meeting of the European Thyroid Association, ETA 2018. 15 Sep 2018-18 Sep 2018. doi: 10.1159/000491542 ⁸⁰ Ciampi, et al., European Thyroid Journal , Vol. 7, Supp. 1, pp 63. Abstract No : OP-09-66. Meeting Info: 41st Annual Meeting of the European Thyroid Association, ETA 2018. 15 Sep 2018-18 Sep 2018. doi: 10.1159/000491542 ⁸¹ Aggarwal, et al., JAMA Oncol . 201 8 Oct 11. doi : 10.1001/jamaoncol.2018.4305. ⁸² Pecce, et al., PLoS Genet . 2018 Oct 15;14(10):e1007678. doi: 10.1371/journal.pgen.1007678. eCollection 2018 Oct. ⁸³ Yousse f et al., Anticancer Res . 2018 Oct;38(10):5627-5634. doi: 10.21873/anticanres.12897 ⁸⁴ Qi, et al. Otolaryngology - Head and Neck Surgery (United States), (October 2018) Vol. 159, No. 1, Supp . Supplement 1, pp. P185. Meeting Info: Annual Meeting of the American Academy of Otolaryngology-Head and Neck Surgery Foundation and OTO Experience, AAO-HNSF 2018. Atlanta, GA, United States. 07 Oct 2018-10 Oct 2018 doi: 10.1177/0194599818787193 ⁸⁵ US Patent No. 10,119,169 ⁸⁶ Subbiah, et al. Cancer Discov . 2018 Jul;8(7):836-849. doi: 10.1158/2159-8290.CD-18-0338.

In some embodiments, dysregulation of the expression or activity or level of the RET gene, RET kinase, or either comprises a splice variation in the RET mRNA that results in an expressed protein that has at least one residue deleted (relative to Alternative splice variants of RET compared to wild-type RET kinase, resulting in constitutive activity of the RET kinase domain.

A "RET kinase inhibitor" as defined herein includes any compound exhibiting RET inhibitory activity. In some embodiments, the RET kinase inhibitor is selective for RET kinase. Exemplary RET kinase inhibitors can exhibit less than about 1000 nM, less than about 500 nM, less than about 200 nM, less than about 100 nM, less than about 50 nM, less than about 25 nM, less than about 10 nM, or less than about 1 nM for RET Kinase inhibitory activity ( _IC50 ), as measured in the assays described herein. In some embodiments, the RET kinase inhibitor can exhibit an inhibitory activity (IC ₅₀ ) against RET kinase of less than about 25 nM, less than about 10 nM, less than about 5 nM, or less than about 1 nM, as assayed herein measured in.

As used herein, a "first RET kinase inhibitor" or "first RET inhibitor" is a RET kinase inhibitor as defined herein, but it does not include a compound of formula I as defined herein or its pharmaceutical acceptable salts or solvates. As used herein, a "second RET kinase inhibitor" or "second RET inhibitor" is a RET kinase inhibitor as defined herein, but it does not include a compound of formula I as defined herein or its pharmaceutical acceptable salts or solvates. When both first and second RET inhibitors are present in the methods provided herein, the first and second RET kinase inhibitors are not the same.

In some embodiments, the dysregulation of the expression or activity or level of the RET gene, RET kinase, or any of them comprises at least one point mutation in the RET gene, which results in the production of one or more amino acid substitutions in the RET gene or An insertion or deletion RET kinase which results in a RET kinase having one or more amino acid insertions or deletions compared to wild-type RET kinase. In some cases, the resulting RET kinase is more resistant to inhibition of its phosphotransferase activity by one or more first RET kinase inhibitors compared to wild-type RET kinase or a RET kinase that does not include the same mutation. Optionally, such mutations do not reduce the sensitivity of cancer cells or tumors having RET kinase to treatment with a compound of formula I or a pharmaceutically acceptable salt or solvate thereof (for example, with the exception of a specific RET inhibitor cancer cells or tumors with resistance mutations). In such embodiments, the RET inhibitor resistance when in the presence of the same first RET kinase inhibitor is compared to wild-type RET kinase or a RET kinase that does not have the same mutation in the presence of the first RET kinase inhibitor. Mutations can result in a RET kinase with one or more of: increased V _max , decreased K _m for ATP, and increased K _D for the first RET kinase inhibitor.

In other embodiments, the dysregulation of the expression or activity or level of the RET gene, the RET kinase, or either comprises at least one point mutation in the RET gene that results in the production of a protein having one or more amine groups compared to wild-type RET kinase. An acid-substituted RET kinase having increased resistance to a compound of formula I or a pharmaceutically acceptable salt or solvate thereof compared to wild-type RET kinase or a RET kinase not comprising the same mutation. In such embodiments, the RET inhibitor resistance mutation can result in a RET kinase that does not have the same mutation compared to wild-type RET kinase or a RET kinase that does not have the same mutation in the presence of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof. RET kinase having one or more of: increased _Vmax , decreased _Km , and decreased _KD in the presence of the same compound of formula I, or a pharmaceutically acceptable salt or solvate thereof.

Examples of RET inhibitor resistance mutations can include, for example, point mutations, insertions, or deletions in and near the ATP binding site in the tertiary structure of RET kinase (e.g., wild-type RET kinase (e.g., the exemplary wild-type RET described herein) amino acid positions 730-733, 738, 756, 758, 804, 805, 807, 810, 811, 881, and 892), including but not limited to gatekeeper residues (such as the amine in wild-type RET kinase) amino acid position 804), P loop residues (eg, amino acid positions 730-737 in wild-type RET kinase), residues in or near the DFG motif (eg, amino acid positions 888-737 in wild-type RET kinase 898) and ATP cleft solvent front amino acid residues (eg, amino acid positions 758, 811 and 892 of wild-type RET kinase). Other examples of these types of mutations include changes in residues that can affect enzyme activity and/or drug binding, including, but not limited to, residues in the activation loop (e.g., amino acids of wild-type RET kinase positions 891-916), residues near or interacting with the activation loop, residues that promote active or inactive enzyme conformation, mutations, deletions and insertions in loops before and within the C-helix Changes (eg, amino acid positions 768-788 in the wild-type RET protein). In some embodiments, the wild-type RET protein is an exemplary wild-type RET kinase described herein. Specific residues or regions of residues that may be altered (and are RET inhibitor resistance mutations) include, but are not limited to, the residues or regions of residues listed in Table 3, wherein based on the human wild-type RET protein sequence (eg SEQ ID NO:1) for numbering. As will be appreciated by those skilled in the art, a reference to a specific amino acid position in SEQ ID NO: 1 can be determined by aligning a reference protein sequence with SEQ ID NO: 1 (e.g., using a software program such as ClustalW2). The amino acid position in a protein sequence. Additional examples of RET inhibitor resistance mutation positions are shown in Table 4. Changes in such residues may include single or multiple amino acid changes, insertions or flanking sequences within a sequence, and deletions or flanking sequences within a sequence. See also J. Kooistra, GK Kanev, OPJ Van Linden, R. Leurs, IJP De Esch and C. De Graaf, “KLIFS: A structural kinase-ligand interaction database,” Nucleic Acids Res. , Vol. 44, No. D1 , pp. D365-D371, 2016, which is incorporated herein by reference in its entirety.

Exemplary sequence of mature human RET protein (SEQ ID NO: 1)

In some embodiments, a RET inhibitor resistance mutation may comprise a dysregulation of the expression or activity or level of the MET gene, MET kinase, or either.

In some embodiments, the compound of formula I and its pharmaceutically acceptable salts and solvates are suitable for use in combination with existing drug therapy (such as other RET kinase inhibitors; such as the first and/or second RET kinase inhibitor ) in combination or as a subsequent or additional (e.g. follow-up) therapy to treat the development of a RET inhibitor resistance mutation (e.g. causing increased resistance to a first RET inhibitor, e.g. a substitution at amino acid position 804, For example, V804M, V804L, or V804E; a substitution at amino acid position 810, such as G810S, G810R, G810C, G810A, G810V, and G810D; and/or one or more of the RET inhibitor resistance mutations listed in Tables 3 and 4) cancer patients. Exemplary first and second RET kinase inhibitors are described herein. In some embodiments, the first or second RET kinase inhibitor may be selected from the group consisting of: cabozantinib, vandetanib, alectinib, apatinib Apatinib, sitravatinib, sorafenib, lenvatinib, ponatinib, dovitinib, sunitinib ( sunitinib), fretinib, LOXO-292, DS-5010, BLU667 and BLU6864.

¹ Yoon et al.,J. Med. Chem. 59(1):358-73, 2016.² U.S. Patent No. 8,629,135.³ Cranston, et al.,Cancer Res. 66(20):10179-87, 2006.⁴ Carlomagno, et al.,Endocr. Rel. Cancer 16(1):233-41, 2009.⁵ Huang et al., Mol. Cancer Ther., 2016 Aug 5. pii: molcanther.0258.2016. [Epub ahead of print].⁶ PCT Patent Application Publication No. WO 2016/127074.⁷ Mamedova et al., Summer Undergraduate Research Programs (SURP) Student Abstracts, University of Oklahoma Health Sciences Center, 2016.⁸ Plenker et al.,Sci. Transl. Med. , 9(394), doi: 10.1126/scitranslmed.aah6144, 2017.⁹ Kraft et al,Cancer Research , 2017, Vol. 77, No. 13, Supp. Supplement 1. Abstract Number: 4882; American Association for Cancer Research Annual Meeting 2017. Washington, DC, United States. 01 Apr 2017-05 Apr 2017.¹⁰ U.S. Patent Application Publication No. 2018/0022732.¹¹ Roskoski and Sadeghi-Nejad,Pharmacol. Res. , 128, 1-17. doi: 10.1016/j.phrs.2017.12.021, 2018.¹² Nakaoku, et al.Nat Commun , 9(1), 625. doi: 10.1038/s41467-018-02994-7, 2018.¹³ Roy et al.Oncologist , 18(10): 1093-1100. doi: 10.1634/theoncologist.2013-0053, 2013表 4. RET 抑制劑抗性突變之其他例示性胺基酸位置

In some embodiments, compounds of formula I, or pharmaceutically acceptable salts and solvates thereof, are useful in the treatment of those identified as having one or more RET inhibitor resistance mutations (causing resistance to a first or second RET inhibitor) Increased resistance, such as a substitution at amino acid position 804, such as V804M, V804L or V804E, or such as a substitution at amino acid position 810, such as G810S, G810R, G810C, G810A, G810V and G810D) cancer. In some embodiments, one or more RET inhibitor resistance mutations occur in a nucleic acid sequence encoding a RET fusion protein (e.g., any of the RET gene fusion proteins described in Table 1), resulting in RET kinase inhibitor resistance The RET fusion protein. In some embodiments, one or more RET inhibitor resistance mutations occur in a nucleic acid sequence encoding a mutant RET protein (e.g., a mutant RET protein having any of the mutations described in Table 2), thereby resulting in RET kinase resistance. Sexual mutant RET protein. Non-limiting examples of RET inhibitor resistance mutations are listed in Tables 3 and 4. Table 3. RET Inhibitor Resistance Mutations

¹ Yoon et al., J. Med. Chem. 59(1):358-73, 2016. ² US Patent No. 8,629,135. ³ Cranston, et al., Cancer Res. 66(20):10179-87, 2006 ⁴ Carlomagno, et al., Endocr. Rel. Cancer 16(1):233-41, 2009. ⁵ Huang et al., Mol. Cancer Ther., 2016 Aug 5. pii: molcanther.0258.2016. [Epub ahead of print]. ⁶ PCT Patent Application Publication No. WO 2016/127074. ⁷ Mamedova et al., Summer Undergraduate Research Programs (SURP) Student Abstracts, University of Oklahoma Health Sciences Center, 2016. ⁸ Plenker et al., Sci. Transl. Med. , 9(394), doi: 10.1126/scitranslmed.aah6144, 2017. ⁹ Kraft et al, Cancer Research , 2017, Vol. 77, No. 13, Supp. Supplement 1. Abstract Number: 4882; American Association for Cancer Research Annual Meeting 2017. Washington, DC, United States. 01 APR 2017-05 APR 2017. ¹⁰ US PATENT Application No. 2018/0022732. ¹¹ Roskoski and Sadeghi-Ne JAD, PHARMACOL. Res. , 128, 1-17. Doi : 10.1016/j.phrs.2017.12.021, 2018. ¹² Nakaoku, et al. Nat Commun , 9(1), 625. doi: 10.1038/s41467-018-02994-7, 2018. ¹³ Roy et al. Oncologist , 18(10): 1093-1100. doi: 10.1634/theoncologist.2013-0053, 2013 Table 4. Other exemplary amino acid positions for RET inhibitor resistance mutations

The carcinogenesis of RET was first described in papillary thyroid carcinoma (PTC) (Grieco et al., Cell , 1990, 60, 557-63), which arises from follicular thyroid cells and is the most common thyroid malignancy . About 20-30% of PTCs have somatic chromosomal rearrangements (translocations or inversions) that link promoters and 5' portions of constitutively expressed unrelated genes to the RET tyrosine kinase domain (Greco et al., QJ Nucl. Med. Mol. Imaging , 2009, 53, 440-54), thus driving its ectopic expression in thyroid cells. The fusion proteins resulting from such rearrangements are referred to as "RET/PTC" proteins. For example, RET/PTC 1 is a fusion between CCDD6 and RET, which is commonly found in papillary thyroid carcinomas. Similarly, RET/PTC3 and RET/PTC4 are both fusions of ELE1 and RET, which are commonly found in papillary thyroid carcinomas, but the fusion events leading to RET/PTC3 and RET/PTC4 produce different proteins with different molecular weights ( See eg Fugazzola et al., Oncogene , 13(5):1093-7, 1996). Some RET fusions related to PTC are not referred to as "RET/PTC", but rather the fusion protein itself. For example, fusions between RET and ELKS and PCM1 are found in PTC, but these fusion proteins are called ELKS-RET and PCM1-RET (see e.g. Romei and Elisei, Front. Endocrinol. (Lausanne) , 3: 54, doi: 10.3389/fendo.2012.00054, 2012). The role of RET-PTC rearrangement in the pathogenesis of PTC has been confirmed in transgenic mice (Santoro et al., Oncogene , 1996, 12, 1821-6). To date, a variety of fusion partners have been identified from PTC and other cancer types, all providing protein/protein interaction domains that induce ligand-independent RET dimerization and constitutive enzymatic activity (see eg Table 1). Recently, a 10.6 Mb interarm inversion in chromosome 10 where the RET gene localizes has been identified in about 2% of lung adenocarcinoma patients, resulting in different variants of the chimeric gene KIF5B-RET (Ju et al., Genome Res. , 2012, 22, 436-45; Kohno et al., 2012, Nature Med. , 18, 375-7; Takeuchi et al., Nature Med. , 2012, 18, 378-81; Lipson et al., 2012, Nature Med. , 18, 382-4). Fusion transcripts were abundantly expressed and all resulting chimeric proteins contained the N-terminal portion of the coiled-coil region of KIF5B that mediates homodimerization, and the entire RET kinase domain. None of the RET-positive patients had other known oncogenic variants (such as EGFR or K-Ras mutations, ALK translocations), supporting the possibility that KIF5B-RET fusions may be driver mutations in lung adenocarcinoma. The oncogenic potential of KIF5B-RET has been demonstrated by transfecting the fusion gene into cultured cell lines: Similar to what was observed in the case of the RET-PTC fusion protein, KIF5B-RET was constitutively phosphorylated and induced NIH-3T3 transformation and IL-3-independent growth of BA-F3 cells. However, other RET fusion proteins have been identified in lung adenocarcinoma patients, such as the CCDC6-RET fusion protein, which has been found to play an important role in the proliferation of the human lung adenocarcinoma cell line LC-2/ad ( Journal of Thoracic Oncology , 2012, 7(12):1872-1876). RET inhibitors have been shown to be useful in the treatment of lung cancers involving RET rearrangements (Drilon, AE et al. J Clin Oncol 33, 2015 (suppl; abstract 8007)). RET fusion proteins have also been identified in colorectal cancer patients (Song Eun-Kee et al., International Journal of Cancer , 2015, 136: 1967-1975).

In addition to RET sequence rearrangements, gain-of-function point mutations in the RET proto-oncogene are also driving oncogenic events, as shown in medullary thyroid carcinoma (MTC), which arises from parafollicular calcitonin-producing cells (de Groot et al., Endocrine Rev. , 2006, 27, 535-60; Wells and Santoro, Clin. Cancer Res. , 2009, 15, 7119-7122). About 25% of MTC are associated with multiple endocrine neoplasia type 2 (MEN2), a group of hereditary cancer syndromes affecting neuroendocrine organs caused by germline activating point mutations in RET. In MEN2 subtypes (MEN2A, MEN2B, and familial MTC/FMTC), mutations in the RET gene have strong phenotype-genotype correlations that define different degrees of MTC aggressiveness and clinical manifestations of the disease. MEN2A syndrome mutations involve one of six cysteine residues (mainly C634) located in the cysteine-rich extracellular region, which cause ligand-independent homodimerization and constitutive RET activation. Patients present with MTC at an early age (onset between 5 and 25 years of age) and may also present with pheochromocytoma (50%) and hyperparathyroidism. MEN2B is primarily caused by the M918T mutation located in the kinase domain. This mutation constitutively activates RET in the monomeric state and alters substrate recognition by the kinase. The MEN2B syndrome is characterized by early onset (<1 year of age) and very aggressive forms of MTC, pheochromocytoma (50% of patients) and ganglioneuroma. In FMTC, the only disease manifestation is MTC, which usually appears in adulthood. Many different mutations have been detected across the entire RET gene. The remaining 75% of MTC cases are sporadic and about 50% of these have RET somatic mutations: the most frequent mutation is M918T, which, like MEN2B, is associated with the most aggressive phenotype. Somatic point mutations of RET have also been described in other tumors, such as colorectal cancer (Wood et al., Science , 2007, 318, 1108-13) and small cell lung cancer ( Jpn. J. Cancer Res. , 1995, 86, 1127-30). In some embodiments, the MTC is a RET fusion positive MTC.

RET signaling components have been found to be expressed in primary breast tumors and to functionally interact with the estrogen receptor-cc pathway in breast tumor cell lines (Boulay et al., Cancer Res. 2008, 68, 3743-51; Plaza-Menacho et al., Oncogene , 2010, 29, 4648-57), and the RET expression and activation caused by GDNF family ligands can play an important role in the perineural invasion of different types of cancer cells (Ito et al., Surgery , 2005, 138, 788-94; Gil et al., J. Natl. Cancer Inst., 2010, 102, 107-18; Iwahashi et al., Cancer, 2002, 94, 167-74).

RET is also expressed in 30-70% of invasive breast cancers, where expression occurs relatively more frequently in estrogen receptor positive tumors (Plaza-Menacho, I. et al., Oncogene , 2010, 29, 4648-4657; Esseghir, S. et al., Cancer Res. , 2007, 67, 11732-11741; Morandi, A. et al., Cancer Res. , 2013, 73, 3783-3795; Gattelli, A., EMBO Mol. Med. , 2013, 5 , 1335-1350).

RET rearrangements have been reported to be identified in a subset of PDXs established from colorectal cancer (patient-derived xenografts). Although the frequency of such events in colorectal cancer patients remains to be defined, these data suggest a role for RET as a target for this indication (Gozgit et al., AACR Annual Meeting 2014). Studies have demonstrated that the RET promoter is frequently methylated in colorectal cancer and identified heterozygous missense mutations predicted to reduce RET expression in 5-10% of cases, suggesting a possible role for RET in sporadic colon cancer. Has some characteristics of tumor suppressors (Luo, Y. et al., Oncogene , 2013, 32, 2037-2047; Sjoblom, T. et al., Science , 2006, 268-274; Cancer Genome Atlas Network, Nature , 2012, 487 , 330-337).

An increasing number of tumor types are now being demonstrated to express large amounts of wild-type RET kinase, which can have an impact on tumor progression and spread. RET is expressed in 50-65% of pancreatic ductal carcinomas and more frequently in metastatic and higher-grade tumors (Ito, Y et al., Surgery , 2005, 138, 788-794; Zeng, Q. et al., J. Int. Med. Res. 2008, 36, 656-664).

Among neoplasms of the hematopoietic lineage, RET is expressed in acute myeloid leukemia (AML) with monocytic differentiation as well as in CMML (Gattei, V. et al., Blood , 1997, 89, 2925-2937; Gattei, V. et al., Ann. Hematol , 1998, 77, 207-210; Camos, M., Cancer Res. 2006, 66, 6947-6954). Recent studies have identified a rare chromosomal rearrangement involving RET in patients with chronic myelomonocytic leukemia (CMML). CMML is often associated with rearrangements of several tyrosine kinases that lead to the expression of chimeric cytosolic tumor proteins, leading to activation of the RAS pathway (Kohlmann, A. et al., J. Clin. Oncol. 2010, 28, 2858-2865) . In the case of RET, gene fusions linking RET to the BCR (BCR-RET) or to the fibroblast growth factor receptor 1 oncogene partner (FGFR1OP-RET) transform in early hematopoietic progenitor cells and enable Maturation of these cells is shifted towards the monocytic pathway, possibly via initiation of RET-mediated RAS signaling (Ballerini, P. et al., Leukemia , 2012, 26, 2384-2389).

RET expression has also been demonstrated in several other tumor types, including prostate cancer, small cell lung cancer, melanoma, renal cell carcinoma, and head and neck tumors (Narita, N. et al., Oncogene , 2009, 28, 3058-3068; Mulligan, LM et al., Genes Chromosomes Cancer , 1998, 21, 326-332; Flavin, R. et al., Urol. Oncol. , 2012, 30, 900-905; Dawson, DM, J Natl Cancer Inst , 1998, 90, 519 -523).

In neuroblastoma, RET expression and activation caused by GFL has a role in tumor cell differentiation, potentially cooperating with other neurotrophic factor receptors to down-regulate N-Myc, which is a sign of poor prognosis ( Hofstra, RM, W. et al., Hum. Genet. 1996, 97, 362-364; Petersen, S. and Bogenmann, E., Oncogene , 2004, 23, 213-225; Brodeur, GM, Nature Ref. Cancer , 2003, 3, 203-216).

Multitargeted inhibitors known to cross-react with RET (Borrello, MG et al., Expert Opin. Ther. Targets , 2013, 17(4), 403-419; International Patent Application Nos. WO 2014/141187, WO 2014/184069 and WO 2015/079251). Such multiple targeting inhibitors (or multiple kinase inhibitors or MKIs) may also be associated with the development of RET inhibitor resistance mutations. See, eg, Q. Huang et al., "Preclinical Modeling of KIF5B-RET Fusion Lung Adenocarcinoma.," Mol. Cancer Ther. , No. 18, pp. 2521-2529, 2016; Yasuyuki Kaneta et al., Abstract B173: Preclinical characterization and antitumor efficacy of DS-5010, a highly potent and selective RET inhibitor, Mol Cancer Ther January 1, 2018 (17) (Supplement 1) B173; DOI: 10.1158/1535-7163.TARG-17-B173, all with It is incorporated herein by reference in its entirety.

Accordingly, provided herein are methods for treating a patient diagnosed with (or identified as having) cancer comprising administering to the patient a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or solvent thereof compound. Also provided herein are methods of treating a patient identified or diagnosed with a RET-associated cancer comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical combination thereof thing. In some embodiments, a regulatory agency-approved (e.g., FDA-approved) test for identifying dysregulation of the RET gene, RET kinase, or expression or activity or amount of either in a patient or in a biopsy sample from a patient has been used or A patient is identified or diagnosed as having a RET-associated cancer by any of the assays or by performing any of the non-limiting examples of the assays described herein. In some embodiments, the tests or assays are provided in kit form. In some embodiments, the cancer is a RET-associated cancer. For example, a RET-associated cancer can be a cancer that includes one or more RET inhibitor resistance mutations. In some embodiments, the compound of Formula I is selected from Examples 1-34 or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula I is selected from the compounds of Examples 1-10, Examples 11-20, Examples 21-34, or pharmaceutically acceptable salts or solvates thereof.

Also provided are methods for treating cancer in a patient in need thereof, the method comprising: (a) detecting RET-associated cancer in the patient; and (b) administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutical thereof acceptable salts or solvates or pharmaceutical compositions thereof. Some embodiments of these methods further comprise administering to the individual another anticancer agent (eg, a second RET inhibitor, a second compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, or immunotherapy). In some embodiments, the individual was previously treated with a first RET inhibitor or was previously treated with another anti-cancer treatment (eg, at least partial tumor resection or radiation therapy). In some embodiments, a regulatory agency-approved (eg, FDA-approved) test or assay for identifying RET gene, RET kinase, or dysregulation of expression or activity or levels of either in a patient or in a biopsy sample from a patient is used A patient is determined to have a RET-associated cancer by performing any of the non-limiting examples of assays described herein. In some embodiments, the tests or assays are provided in kit form. In some embodiments, the cancer is a RET-associated cancer. For example, a RET-associated cancer can be a cancer that includes one or more RET inhibitor resistance mutations.

Also provided are methods of treating a patient comprising performing an assay on a sample obtained from the patient to determine whether the patient has a RET gene, RET kinase, or a disorder in the expression or activity or amount of either, and to determine whether the patient has a RET gene , RET kinase, or a patient with a disorder of expression or activity or content of any of them is administered (for example specifically or selectively administered) a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof or its pharmaceutical composition. Some embodiments of these methods further comprise administering to the individual another anticancer agent (eg, a second RET inhibitor, a second compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, or immunotherapy). In some embodiments of these methods, the individual was previously treated with a first RET inhibitor or was previously treated with another anti-cancer treatment (eg, at least partial tumor resection or radiation therapy). In some embodiments, the patient is a patient suspected of having a RET-related cancer, a patient presenting with one or more symptoms of a RET-related cancer, or a patient at increased risk of developing a RET-related cancer. In some embodiments, the assay uses next-generation sequencing, pyrosequencing, immunohistochemistry, or break apart FISH analysis. In some embodiments, the assay is a regulatory agency approved assay, such as an FDA approved kit. In some embodiments, the assay is a liquid biopsy. Other non-limiting assays can be used in the methods described herein. Other assays are also known in the art. In some embodiments, the dysregulation of the expression or activity or level of the RET gene, RET kinase, or either comprises one or more RET inhibitor resistance mutations.

Also provided is a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, for use in the treatment of RET-associated cancer in a patient by performing an assay on a sample obtained from the patient, such as In vitro assay) to identify or diagnose a RET-associated cancer by the step of determining whether the patient suffers from RET gene, RET kinase, or a dysregulation of the expression or activity or level of any of them, wherein RET gene, RET kinase, or Dysregulation of the expression or activity or level of either identifies the patient as having a RET-associated cancer. Also provided is the use of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of RET-associated cancer in a patient who is analyzed by a sample obtained from the patient Identifying or diagnosing RET-associated cancer by the step of determining whether the patient suffers from RET gene, RET kinase, or expression or activity or level of any of them, wherein RET gene, RET kinase, or any of the expression Disregulation of either activity or level identifies the patient as having a RET-associated cancer. Some embodiments of any of the methods or uses described herein further comprise recording in the patient's clinical record (e.g., a computer readable medium) that the patient was determined to have the RET gene, RET kinase, or any of the following by performing an assay. For any imbalance of performance or activity or content, the compound of formula I or its pharmaceutically acceptable salt or solvate or its pharmaceutical composition should be administered. In some embodiments, the assay uses next-generation sequencing, pyrosequencing, immunohistochemistry, or two-color separation FISH analysis. In some embodiments, the assay is a regulatory agency approved assay, such as an FDA approved kit. In some embodiments, the assay is a liquid biopsy. In some embodiments, the dysregulation of the expression or activity or level of the RET gene, RET kinase, or either comprises one or more RET inhibitor resistance mutations.

Also provided is a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of cancer in a patient in need thereof or in a patient identified or diagnosed with a RET-associated cancer. Also provided is the use of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for treating cancer in a patient identified or diagnosed with a RET-associated cancer. In some embodiments, the cancer is a RET-associated cancer, eg, a RET-associated cancer with one or more RET inhibitor resistance mutations. In some embodiments, by using a regulatory agency-approved (eg, FDA-approved) kit for identifying dysregulation of the expression or activity or amount of the RET gene, RET kinase, or either in a patient or in a biopsy sample from a patient The patient is identified or diagnosed as having a RET-associated cancer. As provided herein, RET-associated cancers include those cancers described herein and known in the art.

Also provided herein are methods for treating a pediatric patient diagnosed with (or identified as having) cancer comprising administering to the pediatric patient a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof. Also provided herein are methods for treating a pediatric patient identified or diagnosed with a RET-associated cancer comprising administering to the pediatric patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, or a medicament thereof combination. In some embodiments, the RET gene, RET kinase, or a dysregulation of the expression or activity or amount of either of the RET gene, RET kinase, or any of them has been approved by a regulatory agency for use (eg, FDA approval) to identify a pediatric patient or a biopsy sample from a pediatric patient. or by performing any of the non-limiting examples of assays described herein to identify or diagnose a pediatric patient with a RET-associated cancer. In some embodiments, the tests or assays are provided in kit form. In some embodiments, the cancer is a RET-associated cancer. For example, a RET-associated cancer can be a cancer that includes one or more RET inhibitor resistance mutations.

Also provided are methods for treating cancer in a pediatric patient in need thereof, the method comprising: (a) determining whether the cancer in the pediatric patient is a RET-associated cancer; and (b) if the cancer is determined to be a RET-associated cancer, reporting to the pediatric The patient is administered a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof. Some embodiments of these methods further comprise administering to the individual another anticancer agent (eg, a second RET inhibitor, a second compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, or immunotherapy). In some embodiments, the individual was previously treated with a first RET inhibitor or was previously treated with another anti-cancer treatment (eg, tumor resection or radiation therapy). In some embodiments, the RET gene, the RET kinase, or a disordered expression or activity or amount of either of the RET gene, RET kinase, or any of them is identified by use of a regulatory agency approved (eg, FDA approved) for identifying a pediatric patient or a biopsy sample from a pediatric patient. A pediatric patient is determined to have a RET-associated cancer by performing any of the tests or assays, or by performing any of the non-limiting examples of assays described herein. In some embodiments, the tests or assays are provided in kit form. In some embodiments, the cancer is a RET-associated cancer. For example, a RET-associated cancer can be a cancer that includes one or more RET inhibitor resistance mutations.

Also provided are methods of treating a pediatric patient comprising performing an assay on a sample obtained from the pediatric patient to determine whether the pediatric patient has a disorder in the expression or activity or level of the RET gene, RET kinase, or either, and to determine A pediatric patient suffering from a disorder of RET gene, RET kinase, or the expression or activity or level of any of them is administered (eg, specifically or selectively administered) a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable compound thereof. Salt or solvate or pharmaceutical composition thereof. Some embodiments of these methods further comprise administering to the individual another anticancer agent (eg, a second RET inhibitor, a second compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, or immunotherapy). In some embodiments of these methods, the individual was previously treated with a first RET inhibitor or was previously treated with another anti-cancer treatment (eg, tumor resection or radiation therapy). In some embodiments, the pediatric patient is a pediatric patient suspected of having a RET-related cancer, a pediatric patient presenting with one or more symptoms of a RET-related cancer, or a pediatric patient at increased risk of developing a RET-related cancer. In some embodiments, the assay uses next-generation sequencing, pyrosequencing, immunohistochemistry, or two-color separation FISH analysis. In some embodiments, the assay is a regulatory agency approved assay, such as an FDA approved kit. Other non-limiting assays can be used in the methods described herein. Other assays are also known in the art. In some embodiments, the dysregulation of the expression or activity or level of the RET gene, RET kinase, or either comprises one or more RET inhibitor resistance mutations.

Also provided is a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, for use in the treatment of RET-associated cancer in a pediatric patient by analysis of a sample obtained from the pediatric patient A method (such as an in vitro assay) for identifying or diagnosing a RET-associated cancer by determining whether the pediatric patient has a dysregulation of the expression or activity or level of the RET gene, RET kinase, or either, in which the RET gene is present , RET kinase, or a dysregulation of the expression or activity or level of any of these identifies the pediatric patient as having a RET-associated cancer. Also provided is a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, for use in the manufacture of a medicament for the treatment of RET-associated cancer in a pediatric patient obtained by treating a pediatric patient with A step in which the obtained sample is analyzed to determine whether the pediatric patient suffers from a dysregulation of the expression or activity or level of the RET gene, RET kinase, or either, to identify or diagnose a RET-associated cancer in which the RET gene, RET A dysregulation of the expression or activity or level of the kinases or either identifies the pediatric patient as having a RET-associated cancer. Some embodiments of any of the methods or uses described herein further comprise recording in the pediatric patient's clinical record (e.g., a computer readable medium) that the pediatric patient was determined to have the RET gene, RET kinase, Or for the disorder of any one of them, the performance or activity or content, the compound of formula I or its pharmaceutically acceptable salt or solvate should be administered. In some embodiments, the assay uses next-generation sequencing, pyrosequencing, immunohistochemistry, or two-color separation FISH analysis. In some embodiments, the assay is a regulatory agency approved assay, such as an FDA approved kit. In some embodiments, the dysregulation of the expression or activity or level of the RET gene, RET kinase, or either comprises one or more RET inhibitor resistance mutations.

Also provided is a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of cancer in a pediatric patient in need thereof or identified or diagnosed with a RET-associated cancer. Also provided is a use of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a cancer in a pediatric patient identified or diagnosed with a RET-associated cancer. In some embodiments, the cancer is a RET-associated cancer, eg, a RET-associated cancer with one or more RET inhibitor resistance mutations. In some embodiments, the RET gene, the RET kinase, or a disordered expression or activity or amount of either of the RET gene, RET kinase, or any of them is identified by use of a regulatory agency approved (eg, FDA approved) for identifying a pediatric patient or a biopsy sample from a pediatric patient. kit to identify or diagnose pediatric patients with RET-associated cancers. As provided herein, RET-associated cancers include those cancers described herein and known in the art.

In some embodiments of any of the methods or uses described herein, the patient has been identified or diagnosed as having a cancer having a dysregulation of the expression or activity or amount of the RET gene, RET kinase, or either. In some embodiments of any of the methods or uses described herein, the patient has a tumor that is positive for a RET gene, a RET kinase, or a dysregulation of the expression or activity or amount of either. In some embodiments of any of the methods or uses described herein, the patient may be a patient with a tumor positive for a RET gene, a RET kinase, or a dysregulation of the expression or activity or level of either. In some embodiments of any of the methods or uses described herein, the patient may be a patient whose tumor has a dysregulation of the expression or activity or amount of the RET gene, RET kinase, or either. In some embodiments of any of the methods or uses described herein, the patient is suspected of having a RET-associated cancer (eg, a cancer with one or more RET inhibitor resistance mutations). In some embodiments, provided herein are methods of treating RET-associated cancer in a patient in need of such treatment, the method comprising a) detecting the expression or activity of the RET gene, RET kinase, or either, in a sample from the patient or an imbalance in its content; and b) administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the dysregulation of the expression or activity or level of the RET gene, RET kinase, or either comprises one or more fusion proteins. Non-limiting examples of RET gene fusion proteins are described in Table 1. In some embodiments, the fusion protein is KIF5B-RET. In some embodiments, the RET gene, RET kinase, or dysregulation of the expression or activity or level of any one of them comprises one or more RET kinase protein point mutations/insertions/deletions. Non-limiting examples of RET kinase protein point mutations/insertions/deletions are described in Table 2. In some embodiments, the RET kinase protein point mutation/insertion/deletion is selected from the group consisting of M918T, M918V, C634W, V804L, V804M, G810S, and G810R. In some embodiments, the dysregulation of the expression or activity or level of the RET gene, RET kinase, or either comprises one or more RET inhibitor resistance mutations. Non-limiting examples of RET inhibitor resistance mutations are described in Tables 3 and 4. In some embodiments, the RET inhibitor resistance mutation is V804M. In some embodiments, the RET inhibitor resistance mutation is G810S. In some embodiments, the RET inhibitor resistance mutation is G810R. In some embodiments, cancers having dysregulation of the expression or activity or amount of the RET gene, RET kinase, or either are determined using a regulatory agency approved (eg, FDA approved) assay or panel. In some embodiments, the tumor positive for RET gene, RET kinase, or dysregulation of the expression or activity or level of either is a tumor positive for one or more RET inhibitor resistance mutations. In some embodiments, tumors having dysregulation of the expression or activity or amount of the RET gene, RET kinase, or either are assayed using a regulatory agency approved (eg, FDA approved) assay or panel.

In some embodiments of any of the methods or uses described herein, the patient has clinical records indicating that the patient has a tumor that has expression or activity of the RET gene, RET kinase, or either, or Dysregulation of content (eg, tumors with one or more RET inhibitor resistance mutations). In some embodiments, clinical records indicate that the patient is treated with one or more of the compounds of Formula I provided herein, or a pharmaceutically acceptable salt or solvate or composition thereof. In some embodiments, the cancer having dysregulation of the expression or activity or level of the RET gene, RET kinase, or either is a cancer with one or more RET inhibitor resistance mutations. In some embodiments, cancers having dysregulation of the expression or activity or amount of the RET gene, RET kinase, or either are determined using a regulatory agency approved (eg, FDA approved) assay or panel. In some embodiments, the tumor positive for RET gene, RET kinase, or dysregulation of the expression or activity or level of either is a tumor positive for one or more RET inhibitor resistance mutations. In some embodiments, tumors having dysregulation of the expression or activity or amount of the RET gene, RET kinase, or either are assayed using a regulatory agency approved (eg, FDA approved) assay or panel.

Also provided is a method of treating a patient comprising administering to a patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, the patient having an expression indicating that the patient has the RET gene, RET kinase, or any of these A clinical record of a disorder in the expression or activity or content of one. Also provided is the use of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of RET-associated cancer in a patient having an indication that the patient has the RET gene, RET Clinical documentation of a disorder in the expression or activity or level of a kinase or either. Some embodiments of these methods and uses may further include: performing an assay (e.g., an in vitro assay) on a sample obtained from a patient to determine whether the patient has the expression or activity of the RET gene, RET kinase, or either or The step of disregulating the level, and recording information that the patient has been identified as having a disorder in the expression or activity or level of the RET gene, RET kinase, or either in the patient's clinical file (eg, computer readable media). In some embodiments, the assay is an in vitro assay. For example, assays use next-generation sequencing, immunohistochemistry, or two-color separation FISH analysis. In some embodiments, assays are regulatory agency-approved, eg, FDA-approved kits. In some embodiments, the assay is a liquid biopsy. In some embodiments, the dysregulation of the expression or activity or level of the RET gene, RET kinase, or either comprises one or more RET inhibitor resistance mutations.

Also provided herein is a method of treating an individual. In some embodiments, the method includes performing an assay on a sample obtained from the individual to determine whether the individual has a disorder in the expression or level of the RET gene, the RET protein, or either. In some such embodiments, the method also includes administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically effective amount thereof to an individual determined to have a disorder in the expression or activity or level of the RET gene, RET protein, or either. acceptable salts or solvates. In some embodiments, the method comprises determining that the individual has a disorder in the expression or amount of the RET gene, the RET protein, or either, via analysis of a sample obtained from the individual. In such embodiments, the method also includes administering to the individual a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the dysregulation of a RET gene, RET kinase protein, or expression or activity thereof is a genetic or chromosomal translocation that results in the expression of a RET fusion protein, such as any of the RET fusion proteins described herein. In some embodiments, the RET fusion can be selected from KIF5B-RET fusion and CCDC6-RET fusion. In some embodiments, the RET gene, the RET kinase protein, or the dysregulation of the expression or activity or level of any one of them is one or more point mutations in the RET gene (such as one or more of the RET point mutations described herein) either). One or more point mutations in the RET gene can result in the translation of, for example, a RET protein with one or more of the following amino acid substitutions: M918T, M918V, C634W, V804L, V804M, G810S, and G810R. In some embodiments, the dysregulation of the expression or activity or level of the RET gene, the RET kinase protein, or any of them is one or more RET inhibitor resistance mutations (such as one or more of the RET inhibitor resistance mutations described herein) any combination of mutations). Some embodiments of these methods further comprise administering to the individual another anticancer agent (eg, a second RET inhibitor, a second compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, or immunotherapy).

In some embodiments, compounds provided herein exhibit brain and/or central nervous system (CNS) permeability. Such compounds are able to cross the blood-brain barrier and inhibit RET kinase in the brain and/or other CNS structures. In some embodiments, the compounds provided herein are capable of crossing the blood-brain barrier in therapeutically effective amounts. For example, treatment of a patient with cancer (eg, a RET-associated cancer, such as a RET-associated brain or CNS cancer) can include administering (eg, oral administration) a compound to the patient. In some such embodiments, the compounds provided herein are useful in the treatment of primary brain tumors or metastatic brain tumors. For example, the compounds can be used to treat one or more of the following: gliomas, such as glioblastoma (also known as glioblastoma multiforme), astrocytoma, oligodendrocyte tumors, ependymomas, and mixed gliomas, meningiomas, medulloblastomas, gangliogliomas, schwannomas (schwannomas), and craniopharyngiomas (see, eg, Tumors listed in Louis, DN et al., Acta Neuropathol 131(6), 803-820 (June 2016). In some embodiments, the brain tumor is a primary brain tumor. In some embodiments, the patient has been previously treated with another anticancer agent (eg, another RET inhibitor (eg, a compound other than a compound of Formula I)) or a multiple kinase inhibitor. In some embodiments, the brain tumor is a metastatic brain tumor. In some embodiments, the patient has been previously treated with another anticancer agent (eg, another RET inhibitor (eg, a compound other than a compound of Formula I)) or a multiple kinase inhibitor.

Also provided are methods (eg, in vitro methods) for selecting treatment of a patient identified or diagnosed with a RET-associated cancer. Some embodiments may further comprise administering a selected treatment to a patient identified or diagnosed with a RET-associated cancer. For example, the treatment of choice may comprise administering a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof. Some embodiments may further comprise the step of performing an assay on a sample obtained from a patient to determine whether the patient has a RET gene, a RET kinase, or a disorder in the expression or activity or amount of any of these, and determining as having RET A patient with dysregulation of the gene, RET kinase, or expression or activity or level of either is identified and diagnosed as having a RET-associated cancer. In some embodiments, the cancer is a RET-associated cancer with one or more RET inhibitor resistance mutations. In some embodiments, by using a regulatory agency-approved (eg, FDA-approved) kit for identifying dysregulation of the expression or activity or amount of the RET gene, RET kinase, or either in a patient or in a biopsy sample from a patient To identify or diagnose patients with RET-associated cancers. In some embodiments, the RET-associated cancer is a cancer described herein or known in the art. In some embodiments, the assay is an in vitro assay. For example, assays use next-generation sequencing, immunohistochemistry, or two-color separation FISH analysis. In some embodiments, assays are regulatory agency-approved, eg, FDA-approved kits. In some embodiments, the assay is a liquid biopsy.

Also provided herein are methods of selecting a treatment for a patient, wherein the methods comprise the step of: performing an assay on a sample obtained from the patient to determine whether the patient has the expression or activity of the RET gene, the RET kinase, or either or Disregulation of the level (eg, one or more RET inhibitor resistance mutations), and identifying or diagnosing a patient with a RET gene, RET kinase, or a dysregulation of the expression or activity or level of either of them as having a RET-associated cancer. Some embodiments further comprise administering a selected treatment to a patient identified or diagnosed with a RET-associated cancer. For example, the treatment of choice may comprise administering to a patient identified or diagnosed with a RET-associated cancer a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the assay is an in vitro assay. For example, assays use next-generation sequencing, immunohistochemistry, or two-color separation FISH analysis. In some embodiments, assays are regulatory agency-approved, eg, FDA-approved kits. In some embodiments, the assay is a liquid biopsy.

Also provided are methods of selecting for treatment of a patient, wherein the methods include selecting, identifying or diagnosing a patient with a RET-associated cancer, and selecting the patient for treatment comprising administering a therapeutically effective amount of a compound of formula I or a pharmaceutical thereof Pharmaceutically acceptable salts or solvates. In some embodiments, identifying or diagnosing a patient with a RET-associated cancer may comprise the step of performing an assay on a sample obtained from the patient to determine whether the patient has the expression or activity of the RET gene, RET kinase, or either or levels, and identifying or diagnosing RET-associated cancers in patients determined to have RET genes, RET kinases, or RET kinases, or disorders in the expression or activity or levels of any of them. In some embodiments, the method of selecting patients for treatment may be used as part of a clinical study involving the administration of various therapies for RET-associated cancers. In some embodiments, a RET-associated cancer is a cancer with one or more RET inhibitor resistance mutations. In some embodiments, the assay is an in vitro assay. For example, assays use next-generation sequencing, immunohistochemistry, or two-color separation FISH analysis. In some embodiments, assays are regulatory agency-approved, eg, FDA-approved kits. In some embodiments, the assay is a liquid biopsy. In some embodiments, the dysregulation of the expression or activity or level of the RET gene, RET kinase, or either comprises one or more RET inhibitor resistance mutations.

In some embodiments of any of the methods or uses described herein, a sample from a patient is used to determine whether the patient has the expression or activity or amount of the RET gene or RET kinase or either. Assays for disorders may include, for example, next-generation sequencing, immunohistochemistry, fluorescence microscopy, two-color separation FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern Northern blotting and PCR-based amplification (such as RT-PCR and quantitative real-time RT-PCR). As is well known in the art, assays are typically performed using, for example, at least one labeled nucleic acid probe or at least one labeled antibody or antigen-binding fragment thereof. Assays Other detection methods known in the art may be used to detect dysregulation of the expression or activity or level of the RET gene, RET kinase, or either (see eg, references cited herein). In some embodiments, the dysregulation of the expression or activity or level of the RET gene, RET kinase, or either comprises one or more RET inhibitor resistance mutations. In some embodiments, the sample is a biological sample or biopsy sample (eg, a paraffin-embedded biopsy sample) from a patient. In some embodiments, the patient is a patient suspected of having a RET-related cancer, a patient with one or more symptoms of a RET-related cancer, and/or a patient at increased risk of developing a RET-related cancer.

In some embodiments, a liquid biopsy (hereafter referred to as a fluid biopsy or a fluid phase biopsy) can be used to identify a dysregulation of the expression or activity or level of the RET gene, RET kinase, or either. See, eg, Karachiliou et al., "Real-time liquid biopsies become a reality in cancer treatment", Ann. Transl. Med. , 3(3):36, 2016. Liquid biopsy methods can be used to detect total tumor burden and/or dysregulation of the expression or activity or amount of the RET gene, RET kinase, or either. Liquid biopsies can be performed on biological samples that are relatively easier to obtain from an individual (eg, via a simple blood draw) and are useful for detecting tumor burden and/or expression or activity or levels of the RET gene, RET kinase, or either Traditional methods of treating the disorder are usually less invasive. In some embodiments, liquid biopsies can be used to detect the presence of dysregulation of the expression or activity or level of the RET gene, RET kinase, or either, at an earlier stage than conventional methods. In some embodiments, biological samples for liquid biopsy may include blood, plasma, urine, cerebrospinal fluid, saliva, sputum, bronchoalveolar lavage, bile, lymph, cystic fluid, stool, ascites, and its combination. In some embodiments, liquid biopsies can be used to detect circulating tumor cells (CTCs). In some embodiments, liquid biopsies can be used to detect cell-free DNA. In some embodiments, the cell-free DNA detected using the liquid biopsy is circulating tumor DNA (ctDNA) derived from tumor cells. Analysis of ctDNA (e.g., using sensitive detection techniques such as, but not limited to, next-generation sequencing (NGS), conventional PCR, digital PCR, or microarray analysis) can be used to identify the RET gene, RET kinase, or either Disorders of expression or activity or content.

In some embodiments, liquid biopsy can be used to detect ctDNA derived from a single gene. In some embodiments, a liquid biopsy can be used to detect genes derived from a plurality of genes (eg, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45). , 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 or more, or any number of genes between these numbers) of ctDNA. In some embodiments, any of a variety of commercially available test panels (eg, commercially available test panels designed to detect dysregulation of the expression or activity or levels of the RET gene, RET kinase, or either) can be used to detect Measure ctDNA derived from multiple genes. Liquid biopsy can be used to detect RET gene, RET kinase, or the expression or activity or content of any of them, including (but not limited to) point mutations or single nucleotide variants (SNV), copy number variants (CNV ), gene fusions (such as translocations or rearrangements), insertions, deletions, or any combination thereof. In some embodiments, liquid biopsies can be used to detect germline mutations. In some embodiments, liquid biopsies can be used to detect somatic mutations. In some embodiments, liquid biopsies can be used to detect primary genetic mutations (eg, primary mutations or primary fusions associated with the initial development of a disease, such as cancer). In some embodiments, liquid biopsies can be used to detect genetic mutations that arise after the development of primary genetic mutations (eg, resistance mutations that arise in response to therapy administered to an individual). In some embodiments, a dysregulation of the expression or activity or amount of the RET gene, RET kinase, or either identified using liquid biopsy is also present in cancer cells (eg, in tumors) in the individual. In some embodiments, any one of the RET genes described herein, RET kinases, or dysregulation of the expression or activity or level of any of them can be detected using liquid biopsy. In some embodiments, genetic mutations identified via liquid biopsy can be used to identify whether an individual is a candidate for a particular treatment. For example, detection of dysregulation of the RET gene, RET kinase, or either in an individual can indicate that the individual will respond to a treatment comprising administration of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof.

Liquid biopsies can be performed at various times during the diagnostic process, monitoring process, and/or therapeutic process to determine one or more clinically relevant parameters, including, but not limited to, disease progression, therapeutic efficacy, or post-treatment administration to an individual. Generation of resistance mutations. For example, a first liquid biopsy can be performed at a first time point and a second liquid biopsy can be performed at a second time point during a diagnostic procedure, a monitoring procedure, and/or a therapeutic procedure. In some embodiments, the first time point can be a time point before the individual is diagnosed with the disease (e.g., when the individual is healthy), and the second time point can be a time point after the individual has developed the disease (e.g., the second time point can be used to diagnose an individual with a disease). In some embodiments, the first time point can be a time point before the individual is diagnosed with a disease (eg, when the individual is healthy), and the individual is subsequently monitored, and the second time point can be a time point after the individual is monitored. In some embodiments, the first time point may be a time point after diagnosing an individual with a disease, and the treatment is subsequently administered to the individual, and the second time point may be a time point after administration of the treatment; herein In such cases, the second time point can be used to assess the efficacy of the treatment (eg, whether a genetic mutation detected at the first time point is significantly reduced or undetectable) or to determine whether a resistance mutation has emerged as a result of the treatment. In some embodiments, the treatment to be administered to a subject may include a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, the relationship between dysregulation of the RET gene can be assessed by assessing cfDNA obtained from a patient at different time points (eg, cfDNA obtained from a patient at a first time point and cfDNA obtained from a patient at a second time point). Allele frequency to determine the efficacy of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, wherein at least one dose of a compound of formula I, or a pharmaceutically acceptable salt thereof, is administered to a patient between a first and a second time point Pharmaceutically acceptable salts or solvates. Some embodiments of these methods can further comprise administering to the patient at least one dose of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, between the first and second time points. For example, the allele frequency (AF) of the dysregulation of the RET gene in cfDNA obtained from the patient at the second time point compared to the allele frequency (AF) of the dysregulation of the RET gene in the cfDNA obtained from the patient at the first time point ( AF) reduction (e.g., 1% to about 99% reduction, 1% to about 95% reduction, 1% to about 90% reduction, 1% to about 85% reduction, 1% to about 80% reduction, 1% to about 75% reduction, 1% reduction to approximately 70% reduction, 1% reduction to approximately 65% reduction, 1% reduction to approximately 60% reduction, 1% reduction to approximately 55% reduction, 1% reduction to approximately 50% reduction, 1 % reduction to about 45% reduction, 1% reduction to about 40% reduction, 1% reduction to about 35% reduction, 1% reduction to about 30% reduction, 1% reduction to about 25% reduction, 1% reduction to about 20% reduction % reduction, 1% reduction to about 15% reduction, 1% reduction to about 10% reduction, 1% to about 5% reduction, about 5% to about 99% reduction, about 10% to about 99% reduction, about 15% reduction to about 99% reduction, about 20% to about 99% reduction, about 25% to about 99% reduction, about 30% to about 99% reduction, about 35% to about 99% reduction, about 40% to about 99% reduction , about 45% to about 99% reduction, about 50% to about 99% reduction, about 55% to about 99% reduction, about 60% to about 99% reduction, about 65% to about 99% reduction, about 70% to About 99% reduction, about 75% to about 95% reduction, about 80% to about 99% reduction, about 90% to about 99% reduction, about 95% to about 99% reduction, about 5% to about 10% reduction , about 5% to about 25% reduction, about 10% to about 30% reduction, about 20% to about 40% reduction, about 25% to about 50% reduction, about 35% to about 55% reduction, about 40% to about 40% reduction About 60% reduction, about 50% reduction to about 75% reduction, about 60% reduction to about 80% reduction, or about 65% to about 85% reduction) indicates that the compound of formula I or a pharmaceutically acceptable salt or solvate thereof The substance is effective in the individual. In some embodiments, AF is reduced such that the level is below the detection limit of the instrument. Alternatively, the allele frequency (AF) of the dysregulation of the RET gene in cfDNA obtained from the patient at a second time point compared to the allele frequency (AF) of the dysregulation of the RET gene in cfDNA obtained from the patient at the first time point An increase indicates that the compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, is not effective in the individual (eg, the individual develops a resistance mutation to the compound of formula I, or a pharmaceutically acceptable salt or solvate thereof). Some embodiments of these methods may further comprise administering an additional dose of a compound of formula I or a pharmaceutically acceptable salt thereof to the patient in whom it is determined that the compound of formula I or a pharmaceutically acceptable salt or solvate thereof is effective or solvates. Some embodiments of these methods may further comprise administering a different treatment (e.g., excluding the compound of Formula I or its pharmaceutically acceptable The treatment of administration of salts or solvates of , in the form of monotherapy).

In some examples of these methods, the time difference between the first and second points in time can be from about 1 day to about 1 year, from about 1 day to about 11 months, from about 1 day to about 10 months, from about 1 day 1 day to about 9 months, about 1 day to about 8 months, about 1 day to about 7 months, about 1 day to about 6 months, about 1 day to about 5 months, about 1 day to about 4 months month, about 1 day to about 3 months, about 1 day to about 10 weeks, about 1 day to about 2 months, about 1 day to about 6 weeks, about 1 day to about 1 month, about 1 day to about 1 month 25 days, about 1 day to about 20 days, about 1 day to about 15 days, about 1 day to about 10 days, about 1 day to about 5 days, about 2 days to about 1 year, about 5 days to about 1 year , about 10 days to about 1 year, about 15 days to about 1 year, about 20 days to about 1 year, about 25 days to about 1 year, about 1 month to about 1 year, about 6 weeks to about 1 year, about 2 months to about 1 year, about 3 months to about 1 year, about 4 months to about 1 year, about 5 months to about 1 year, about 6 months to about 1 year, about 7 months to about 1 year year, about 8 months to about 1 year, about 9 months to about 1 year, about 10 months to about 1 year, about 11 months to about 1 year, about 1 day to about 7 days, about 1 day to About 14 days, about 5 days to about 10 days, about 5 days to about 20 days, about 10 days to about 20 days, about 15 days to about 1 month, about 15 days to about 2 months, about 1 week to about 1 month, about 2 weeks to about 1 month, about 1 month to about 3 months, about 3 months to about 6 months, about 4 months to about 6 months, about 5 months to about 8 months months, or from about 7 months to about 9 months. In some embodiments of these methods, a patient can be pre-identified as having a cancer with RET gene dysregulation (eg, any of the examples of RET gene dysregulation described herein). In some embodiments of these methods, the patient can be pre-diagnosed as having any of the types of cancer described herein. In some embodiments of these methods, the patient may have one or more metastases (eg, one or more brain metastases).

In some of the above embodiments, the cfDNA comprises ctDNA, such as RET-associated ctDNA. For example, cfDNA is ctDNA, such as RET-associated ctDNA. In some embodiments, at least some portion of the cfDNA is determined to be RET-associated ctDNA, eg, sequenced and/or quantified amounts of total cfDNA are determined to have RET fusions and/or RET resistance mutations.

In the field of medical oncology, it is routine practice to treat individual cancer patients with a combination of different treatment modalities. In medical oncology, other components of such combination therapies or therapies other than the compositions provided herein can be, for example, surgery, radiation therapy, and chemotherapeutic agents, such as other kinase inhibitors, signal transduction inhibitors, and / or monoclonal antibodies. For example, surgery can be open surgery or minimally invasive surgery. Accordingly, the compound of formula I or a pharmaceutically acceptable salt or solvate thereof may also be suitable as an adjuvant for cancer therapy, i.e. it may be used in combination with one or more other therapies or therapeutic agents, e.g. by means of the same or Chemotherapeutic agents working by different mechanisms of action. In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, may be administered prior to the administration of other therapeutic agents or other therapies. For example, one or more doses of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, may be administered to a patient in need thereof for a period of time and then undergo at least partial resection of the tumor. In some embodiments, treatment with one or more doses of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, reduces tumor size (eg, tumor burden) prior to at least partial resection of the tumor. In some embodiments, one or more doses of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, may be administered over a period of time and one or more rounds of radiation therapy to a patient in need thereof. In some embodiments, treatment with one or more doses of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, prior to one or more rounds of radiation therapy reduces tumor size (e.g., tumor burden ).

In some embodiments, the patient has cancer (e.g., locally advanced or metastatic tumors) that responds to standard therapy (e.g., administration of a chemotherapeutic agent, such as a first RET inhibitor or multiple kinase inhibitor, immunotherapy, or radiation (e.g. radioactive iodine)) are refractory or intolerable. In some embodiments, the patient has cancer (e.g., a locally advanced or metastatic tumor) that has responded to prior therapy (e.g., administration of a chemotherapeutic agent, such as a first RET inhibitor or multiple kinase inhibitor, immunotherapy, or radiation ( For example radioactive iodine)) is refractory or intolerable. In some embodiments, the patient has cancer for which there is no standard therapy (eg, locally advanced or metastatic tumors). In some embodiments, the patient is not treated with a RET kinase inhibitor. For example, the patient is not being treated with a selective RET kinase inhibitor. In some embodiments, the patient is not naïve to treatment with a RET kinase inhibitor.

In some embodiments, the patient has undergone prior therapy. In some embodiments, prior to treatment with a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, patients with NSCLC (e.g., RET fusion-positive NSCLS) have received platinum-based chemotherapy, Treatment with PD-1/PDL1 immunotherapy or both. In some embodiments, prior to treatment with a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, a patient with thyroid cancer (eg, RET fusion-positive thyroid cancer) has received sorafenib , Lenvatinib and radioactive iodine treatment by one or more. In some embodiments, prior to treatment with a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, a patient with colorectal cancer (eg, RET fusion-positive colorectal cancer) has received a fluorine-based Treatment with pyrimidine chemotherapy (in the presence or absence of anti-VEGF-directed therapy or anti-EGFR-directed therapy). In some embodiments, prior to treatment with a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, a patient with pancreatic cancer (eg, RET fusion-positive pancreatic cancer) has received fluorine-based Treatment by one or more of pyrimidine chemotherapy, gemcitabine-based chemotherapy and S-1 chemotherapy. In some embodiments, prior to treatment with a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, a patient with breast cancer (eg, RET fusion-positive breast cancer) has received anthracycline, purple Treatment by one or more of taxane, HER2-directed therapy and hormone therapy. In some embodiments, prior to treatment with a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, a patient with MTC (e.g., a RET fusion-positive MTC cancer) has received cabozantinib and Treatment by one or more of vandetanib.

In some embodiments of any of the methods described herein, the compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, is combined with a therapeutically effective amount of at least one selected from one or more other therapies or therapeutics (e.g. Chemotherapeutic) agents are administered in combination with other therapeutic agents.

Non-limiting examples of other therapeutic agents include: other therapeutic agents targeting RET (i.e., first or second RET kinase inhibitors), other kinase inhibitors (e.g., therapeutic agents targeting receptor tyrosine kinases ( e.g. Trk inhibitors or EGFR inhibitors)), signal transduction pathway inhibitors, checkpoint inhibitors, modulators of apoptotic pathways (e.g. obataclax); cytotoxic chemotherapeutics, angiogenesis targeting therapy, immune targeting agents (including immunotherapy), and radiation therapy.

In some embodiments, other RET-targeting therapeutic agents are multiple kinase inhibitors that exhibit RET inhibitory activity. In some embodiments, other therapeutic inhibitors targeting RET are selective for RET kinase. Exemplary RET kinase inhibitors can exhibit less than about 1000 nM, less than about 500 nM, less than about 200 nM, less than about 100 nM, less than about 50 nM, less than about 25 nM, less than about 10 nM, or less than about 1 nM for RET Kinase inhibitory activity ( _IC50 ), as measured in the assays described herein. In some embodiments, the RET kinase inhibitor can exhibit an inhibitory activity (IC ₅₀ ) against RET kinase of less than about 25 nM, less than about 10 nM, less than about 5 nM, or less than about 1 nM, as provided herein measured in the analysis.

Non-limiting examples of therapeutic agents targeting RET (e.g., a first RET inhibitor or a second RET inhibitor) include alectinib (9-ethyl-6,6-dimethyl-8-[4-( Morpholin-4-yl)piperidin-1-yl]-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile); Amuvatinib )(MP470, HPK56)(N-(1,3-benzodioxol-5-ylmethyl)-4-([1]benzofuro[3,2-d]pyrimidine-4 -yl)piperazine-1-thiocarbamide); Apatinib (YN968D1) (N-[4-(1-cyanocyclopentyl)phenyl-2-(4-pyridinemethyl base) amino-3-nicotinamide); cabozantinib (Cometriq XL-184) (N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl )-N'-(4-fluorophenyl)cyclopropane-1,1-dimethylamide); Dovitinib (TKI258; GFKI-258; CHIR-258) ((3Z)-4-amino- 5-fluoro-3-[5-(4-methylpiperazin-1-yl)-1,3-dihydrobenzimidazol-2-ylidene]quinolin-2-one); Famitinib ( 5-[2-(Diethylamino)ethyl]-2-[(Z)-(5-fluoro-2-oxo-1H-indole-3-ylidene)methyl]-3- Methyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4-one); Fedratinib (SAR302503, TG101348) (N-(2-methyl-2 -Propanyl)-3-{[5-methyl-2-({4-[2-(1-pyrrolidinyl)ethoxy]phenyl}amino)-4-pyrimidinyl]amino}benzene sulfonamide); fretinib (XL880, EXEL-2880, GSK1363089, GSK089) (N1'-[3-fluoro-4-[[6-methoxy-7-(3-morpholinopropoxy )-4-quinolinyl]oxy]phenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dimethylamide); Fusitinib (fostamantinib) (R788) (2H- Pyrido[3,2-b]-1,4-oxazin-3(4H)-one, 6-[[5-fluoro-2-[(3,4,5-trimethoxyphenyl)amino ]-4-pyrimidinyl]amino]-2,2-dimethyl-4-[(phosphonoyloxy)methyl]-, sodium salt (1:2)); ilorasertib ( ABT-348)(1-(4-(4-amino-7-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)thieno[3,2-c]pyridine-3 -yl)phenyl)-3-(3-fluorophenyl)urea); Lenvatinib (E7080, Lenvima) (4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy] -7-methoxy-6-quinoline carboxamide); motesanib (AMG 706) (N-(3,3-dimethyl-2,3-dihydro-1H-indole -6-yl)-2-[(pyridin-4-ylmethyl)amino]pyridine-3-carboxamide); nintedanib (3-Z-[1-(4-(N -((4-Methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl -2-indolinone); ponatinib (AP24534) (3-(2-imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4 -[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]benzamide); PP242 (torkinib) (2-[4 -amino-1-(1-methylethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-1H-indol-5-ol); quinzatinib )(1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-(7-(2-(N-morpholinyl)ethoxy)benzo[d]imidazole and[2,1-b]thiazol-2-yl)phenyl)urea); Regorafenib (BAY 73-4506, Stivarga) (4-[4-({[ 4-Chloro-3-(trifluoromethyl)phenyl]aminoformyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-formamide hydrate); RXDX-105 (CEP-32496, agerafenib) (1-(3-((6,7-dimethoxyquinazolin-4-yl)oxy)phenyl)-3-(5-(1 ,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea); Semaxanib (SU5416)((3Z)-3-[(3,5 -Dimethyl-1H-pyrrol-2-yl)methylene]-1,3-dihydro-2H-indol-2-one); Stetinib (MGCD516, MG516) (N-(3- Fluoro-4-{[2-(5-{[(2-methoxyethyl)amino]methyl-2-pyridyl)thieno[3,2-b]pyridin-7-yl]oxy }phenyl)-N'-(4-fluorophenyl)-1,1-cyclopropanedimethylamide); Sorafenib (BAY 43-9006) (4-[4-[[[[4- Chloro-3-(trifluoromethyl)phenyl]amino]carbonyl]amino]phenoxy]-N-methyl-2-pyridinecarboxamide); vandetanib (N-(4-bromo -2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine); Fantalanib (vatalanib)( PTK787, PTK/ZK, ZK222584) (N-(4-chlorophenyl)-4-(pyridin-4-ylmethyl)phthalazin-1-amine); AD-57 (N-[4-[4- Amino-1-(1-methylethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]-N'-[3-(trifluoromethyl)phenyl ]-urea); AD-80 (1-[4-(4-amino-1-prop-2-ylpyrazolo[3,4-d]pyrimidin-3-yl)phenyl]-3-[ 2-fluoro-5-(trifluoromethyl)phenyl]urea); AD-81 (1-(4-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d ]pyrimidin-3-yl)phenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea); ALW-II-41-27 (N-(5-((4-( (4-Ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)aminoformyl)-2-methylphenyl)-5-(thiophen-2-yl) Nicotinamide); BPR1K871 (1-(3-chlorophenyl)-3-(5-(2-((7-(3-(dimethylamino)propoxy)quinazoline-4- CLM3 (1-phenylethyl-N-(1-phenylethyl)-1H-pyrazolo[3,4-d]pyrimidine- 4-amine); EBI-907 (N-(2-chloro-3-(1-cyclopropyl-8-methoxy-3H-pyrazolo[3,4-c]isoquinolin-7-yl )-4-fluorophenyl)-3-fluoropropane-1-sulfonamide); NVP-AST-487 (N-[4-[(4-ethyl-1-piperazinyl)methyl]-3 -(trifluoromethyl)phenyl]-N'-[4-[[6-(methylamino)-4-pyrimidinyl]oxy]phenyl]-urea); NVP-BBT594 (BBT594)( 5-((6-Acetamidopyrimidin-4-yl)oxy)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl) phenyl)indoline-1-carboxamide); PD173955 (6-(2,6-dichlorophenyl)-8-methyl-2-(3-methylthioanilino)pyrido[2 ,3-d]pyrimidin-7-one); PP2 (4-amino-5-(4-chlorophenyl)-7-(dimethylethyl)pyrazolo[3,4-d]pyrimidine) ; PZ-1 (N-(5-(tert-butyl)isoxazol-3-yl)-2-(4-(5-(1-methyl-1H-pyrazol-4-yl)-1H -benzo[d]imidazol-1-yl)phenyl)acetamide); RPI-1 (1,3-dihydro-5,6-dimethoxy-3-[(4-hydroxyphenyl) Methylene]-H-indol-2-one; (3E)-3-[(4-hydroxyphenyl)methylene]-5,6-dimethoxy-1H-indol-2-one ); SGI-7079 (3-[2-[[3-fluoro-4-(4-methyl-1-piperazinyl)phenyl]amino]-5-methyl-7H-pyrrolo[2, 3-d]pyrimidin-4-yl]-phenylacetonitrile); SPP86 (1-isopropyl-3-(phenylethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine) ; SU4984 (4-[4-[(E)-(2-oxo-1H-indol-3-ylidene)methyl]phenyl]piperazine-1-carbaldehyde); sunitib (sunitinb )(SU11248)(N-(2-Diethylaminoethyl)-5-[(Z)-(5-fluoro-2-oxo-1H-indole-3-ylidene)methyl]- 2,4-Dimethyl-1H-pyrrole-3-carboxamide); TG101209 (N-tert-butyl-3-(5-methyl-2-(4-(4-methylpiperazine-1 -yl)phenylamino)pyrimidin-4-ylamino)benzenesulfonamide); Withaferin A (Withaferin A)((4β,5β,6β,22R)-4,27-dihydroxy-5, 6:22,26-diethoxyergosta-2,24-diene-1,26-dione); XL-999 ((Z)-5-((1-ethylpiperidine-4- base)amino)-3-((3-fluorophenyl)(5-methyl-1H-imidazol-2-yl)methylene)indolin-2-one); BPR1J373 (5-phenylthiazole -2-ylamine-pyrimidine derivatives); CG-806 (CG'806); DCC-2157; GTX-186; HG-6-63-01 ((E)-3-(2-(4-chloro- 1H-pyrrolo[2,3-b]pyridin-5-yl)vinyl)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl )phenyl)-4-methylbenzamide); SW-01 (Cyclobenzaprine hydrochloride (Cyclobenzaprine hydrochloride)); XMD15-44 (N-(4-((4-ethylpiperazine-1- yl)methyl)-3-(trifluoromethyl)phenyl)-4-methyl-3-(pyridin-3-ylethynyl)benzamide (generated from structure)); Y078-DM1 (generated from Antibody-drug conjugates composed of RET antibody (Y078) linked to a derivative of the cytotoxic agent maytansine); Y078-DM4 (an antibody composed of a RET antibody (Y078) linked to a derivative of the cytotoxic agent maytansine drug conjugates); ITRI-305 (D0N5TB, DIB003599); BLU-667 ((1S,4R)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl) Pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl ) cyclohexane-1-carboxamide); BLU6864; DS-5010 (BOS172738); GSK3179106; GSK3352589; NMS-E668; TAS0286/HM05; TPX0046; ) Ethoxy)-5-(trifluoromethyl)phenyl)-2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2 -fluorophenyl)acetamide.

Other examples of therapeutic agents targeting RET (e.g., a first RET kinase inhibitor or a second RET kinase inhibitor) include 5-amino-3-(5-cyclopropylisoxazol-3-yl)-1- Isopropyl-1H-pyrazole-4-carboxamide; 3-(5-cyclopropylisoxazol-3-yl)-1-isopropyl-1H-pyrazolo[3,4-d] Pyrimidin-4-amine; 3-((6,7-dimethoxyquinazolin-4-yl)amino)-4-fluoro-2-cresol; N-(5-(tert-butyl) Isoxazol-3-yl)-2-(4-(imidazo[1,2-a]pyridin-6-yl)phenyl)acetamide; N-(5-(tert-butyl)isoxane Azol-3-yl)-2-(3-(imidazo[1,2-b]pyridazin-6-yloxy)phenyl)acetamide; N-(2-fluoro-5-trifluoroform phenyl)-N'-{4'-[(2''-benzamido)pyridin-4''-ylamino]phenyl}urea; 2-amino-6-{[2- (4-Chlorophenyl)-2-oxoethyl]sulfonyl}-4-(3-thienyl)pyridine-3,5-dicarbonitrile; and 3-arylureidobenzylidene -Indolin-2-one.

其中R₁ 為C₆ -C₂₄ 烷基或聚乙二醇；或其醫藥學上可接受之鹽形式。在一些實施例中，其他RET抑制劑為4-{5-[雙-(氯乙基)-胺基]-1-甲基-1H-苯并咪唑-2-基}丁酸十二烷酯。Other examples of other RET kinase inhibitors include the inhibitors described in US Patent Nos. 9,150,517 and 9,149,464 and International Publication No. WO 2014075035, both of which are incorporated herein by reference. For example, in some embodiments, other RET inhibitors are compounds of Formula I:

Wherein R ₁ is C ₆ -C ₂₄ alkyl or polyethylene glycol; or a pharmaceutically acceptable salt thereof. In some embodiments, the other RET inhibitor is dodecyl 4-{5-[bis-(chloroethyl)-amino]-1-methyl-1H-benzimidazol-2-yl}butyrate .

其中環A及B各自獨立地選自芳基、雜芳基、環烷基及雜環基； 各L¹ 及L² 獨立地選自一鍵、-(C1-C6伸烷基)-、-(C2-C6伸烯基)-、-(C2-C6伸炔基)-、-(C1-C6鹵基伸烷基)-、-(C1-C6伸雜烷基)-、-C(O)-、-O-、-S-、-S(O)、-S(O)₂ -、-N(R¹ )-、-O-(C1-C6伸烷基)-、-(C1-C6伸烷基)-O-、-N(R¹ )-C(O)-、-C(O)N(R¹ )-、-(C1-C6伸烷基)-N(R¹ )-、-N(R¹ )-(C1-C6伸烷基)-、-N(R¹ )-C(O)-(C1-C6伸烷基)-、-(C1-C6伸烷基)-N(R¹ )-C(O)-、-C(O)-N(R¹ )-(C1-C6伸烷基)-、-(C1-C6伸烷基)-C(O)-N(R¹ )-、-N(R¹ )-S(O)₂ -、-S(O)₂ -N(R¹ )-、-N(R¹ )-S(O)₂ -(C1-C6伸烷基)-及-S(O)₂ -N(R¹ )-(C1-C6伸烷基)-；其中各伸烷基、伸烯基、伸炔基、鹵基伸烷基及伸雜烷基獨立地經R'取代0-5次； 各R^A 及R^B 獨立地選自C1-C6烷基、C1-C6烷氧基、鹵基、C1-C6鹵烷基、C1-C6羥基烷基、C1-C6雜烷基及-N(R¹ )(R¹ )；其中各烷基、烷氧基、鹵烷基、羥基烷基及羥基烷基獨立地經Ra取代0-5次； 各R^C 及R^D 係獨立地選自C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、鹵基、C1-C6雜烷基、C1-C6鹵烷基、C1-C6鹵烷氧基、C1-C6羥基烷基、環烷基、芳基、雜芳基、芳基氧基、芳烷基、雜環基、雜環基烷基、硝基、氰基、-C(O)R¹ 、-OC(O)R¹ 、-C(O)OR¹ 、-(C1-C6伸烷基)-C(O)R¹ 、-SR¹ 、-S(O)₂ R¹ 、-S(O)₂ -N(R¹ )(R¹ )、-(C1-C6伸烷基)-S(O)₂ R¹ 、-(C1-C6伸烷基)-S(O)₂ -N(R¹ )(R¹ )、-N(R¹ )(R¹ )-C(O)-N(R¹ )(R¹ )-N(R¹ )-C(O)R¹ 、-N(R¹ )-C(O)OR¹ 、-(C1-C6伸烷基)-N(R¹ )-C(O)R¹ 、-N(R¹ )S(O)₂ R¹ 及-P(O)(R¹ )(R¹ )；其中烷基、烯基、炔基烷氧基、雜烷基、鹵烷基、鹵烷氧基、羥基烷基、環烷基、芳基、雜芳基、芳基氧基、芳烷基、雜環基及雜環基烷基中之每一者獨立地經R^a 取代0-5次；或2個R^C 或2個R^D 與其所連接之碳原子共同形成獨立地經R^a 取代0-5次之環烷基或雜環基環； 各R¹ 係獨立地選自氫、羥基、鹵基、硫醇、C1-C6烷基、C1-C6硫烷基、C1-C6烷氧基、C1-C6鹵烷基、C1-C6羥基烷基、C1-C6雜烷基、環烷基、環烷基烷基、雜芳基烷基、雜環基及雜環基烷基，其中烷基、硫烷基、烷氧基、鹵烷基、羥基烷基、雜烷基、環烷基、環烷基烷基、雜芳基烷基、雜環基及雜環基烷基中之每一者獨立地經R^b 取代0-5次，或2個R¹ 與其所連接之原子共同形成獨立地經R^b 取代0-5次之環烷基或雜環基環； 各R^a 及R^b 獨立地為C1-C6烷基、鹵基、羥基、C1-C6鹵烷基、C1-C6雜烷基、C1-C6羥基烷基、C1-C6烷氧基、環烷基、雜環基或氰基，其中烷基、鹵烷基、雜烷基、羥基烷基、烷氧基、環烷基及雜環基中之每一者獨立地經R'取代0-5次； 各R'為C1-C6烷基、C1-C6雜烷基、鹵基、羥基、C1-C6鹵烷基、C1-C6羥基烷基、環烷基或氰基；或2個R'與其所連接之原子共同形成環烷基或雜環基環； m為0、1、2或3； n為0、1或2；及 p及q各自獨立地為0、1、2、3或4。舉例而言，RET抑制劑可選自由以下組成之群：

，或其醫藥學上可接受之鹽。Other examples of other RET kinase inhibitors include the inhibitors described in International Publication No. WO 2016127074, which is incorporated herein by reference. For example, in some embodiments, the other RET inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein:

Wherein the rings A and B are each independently selected from aryl, heteroaryl, cycloalkyl and heterocyclyl; each L ^{and L} are independently selected from a bond, -(C1-C6 alkylene)-, - (C2-C6alkenyl)-,-(C2-C6alkynyl)-,-(C1-C6haloalkylene)-,-(C1-C6heteroalkylene)-,-C(O) -, -O-, -S-, -S(O), -S(O) ₂ -, -N(R ¹ )-, -O-(C1-C6 alkylene)-, -(C1-C6 Alkylene)-O-, -N(R ¹ )-C(O)-, -C(O)N(R ¹ )-, -(C1-C6 Alkylene)-N(R ¹ )-, -N(R ¹ )-(C1-C6 alkylene)-, -N(R ¹ )-C(O)-(C1-C6 alkylene)-, -(C1-C6 alkylene)-N (R ¹ )-C(O)-, -C(O)-N(R ¹ )-(C1-C6 alkylene)-, -(C1-C6 alkylene)-C(O)-N( R ¹ )-, -N(R ¹ )-S(O) ₂ -, -S(O) ₂ -N(R ¹ )-, -N(R ¹ )-S(O) ₂ -(C1-C6 alkylene)- and -S(O) ₂ -N(R ¹ )-(C1-C6 alkylene)-; each of alkylene, alkenylene, alkynylene, haloalkylene and hetero Alkyl is independently substituted by R' for 0-5 times; each R ^A and R ^B are independently selected from C1-C6 alkyl, C1-C6 alkoxy, halo, C1-C6 haloalkyl, C1-C6 hydroxyl Alkyl, C1-C6 heteroalkyl and -N(R ¹ )(R ¹ ); wherein each alkyl, alkoxy, haloalkyl, hydroxyalkyl and hydroxyalkyl are independently substituted by Ra for 0-5 times ; Each R ^C and R ^D are independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halo, C1-C6 heteroalkyl, C1-C6 Haloalkyl, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, cycloalkyl, aryl, heteroaryl, aryloxy, aralkyl, heterocyclyl, heterocyclylalkyl, nitrate group, cyano group, -C(O)R ¹ , -OC(O)R ¹ , -C(O)OR ¹ , -(C1-C6alkylene)-C(O)R ¹ , -SR ¹ , -S(O) ₂ R ¹ , -S(O) ₂ -N(R ¹ )(R ¹ ), -(C1-C6 alkylene)-S(O) ₂ R ¹ , -(C1-C6 Alkyl)-S(O) ₂ -N(R ¹ )(R ¹ ), -N(R ¹ )(R ¹ )-C(O)-N(R ¹ )(R ¹ )-N(R ¹ )-C(O)R ¹ , -N(R ¹ )-C(O)OR ¹ , -(C1-C6 alkylene)-N(R ¹ )-C(O)R ¹ , -N(R ¹ ) S(O) ₂ R ¹ and -P(O)(R ¹ )(R ¹ ); where alkyl, alkenyl, alkynylalkoxy, heteroalkyl, haloalkyl, haloalkoxy, Each of hydroxyalkyl, cycloalkyl, aryl, heteroaryl, aryloxy, aralkyl, heterocyclyl, and heterocyclylalkyl is independently substituted by ^R 0-5 times; or 2 R ^C or 2 R ^D together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl ring independently substituted by R ^a 0-5 times; each R ¹ is independently selected from hydrogen, hydroxyl, halogen group, thiol, C1-C6 alkyl, C1-C6 sulfanyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl, cycloalkyl, Cycloalkylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl, wherein alkyl, sulfanyl, alkoxy, haloalkyl, hydroxyalkyl, heteroalkyl, cycloalkyl, Each of cycloalkylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl is independently substituted 0-5 times by ^R , or ² R and the atoms to which they are attached together form an independent 0-5 cycloalkyl or heterocyclyl rings substituted by R ^b ; each R ^a and R ^b are independently C1-C6 alkyl, halo, hydroxyl, C1-C6 haloalkyl, C1-C6 hetero Alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, cycloalkyl, heterocyclyl or cyano, where alkyl, haloalkyl, heteroalkyl, hydroxyalkyl, alkoxy, cycloalkane Each of the radical and the heterocyclic group is independently substituted by R' for 0-5 times; each R' is C1-C6 alkyl, C1-C6 heteroalkyl, halo, hydroxyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl or cyano; or 2 R' and the atoms they are attached to form a cycloalkyl or heterocyclyl ring; m is 0, 1, 2 or 3; n is 0, 1 or 2; and p and q are each independently 0, 1, 2, 3 or 4. For example, RET inhibitors may be selected from the group consisting of:

, or a pharmaceutically acceptable salt thereof.

R1及R2獨立地為氫或選自以下之視情況經取代之基團：直鏈或分支鏈(C₁ -C₆ )烷基、(C₃ -C₆ )環烷基及COR'，其中R'為選自直鏈或分支鏈(C₁ -C₆ )烷基及(C₃ -C₆ )環烷基之視情況經取代之基團； R3為氫或選自以下之視情況經取代之基團：直鏈或分支鏈(C₁ -C₆ )烷基、(C₂ -C₆ )烯基、(C₂ -C₆ )炔基、(C₃ -C₆ )環烷基、芳基、雜芳基及3至7員雜環基環； R4為氫或選自以下之視情況經取代之基團：直鏈或分支鏈(C₁ -C₆ )烷基、(C₂ -C₆ )烯基、芳基、雜芳基或雜環基； A為5或6員雜芳基環或苯環； B為選自雜芳基、(C₅ -C₆ )環烷基及雜環基環或苯環之5或6員環；其中環A與環B稠合在一起以形成雙環系統，其包含與6員芳族或5至6員雜芳族、(C₅ -C₆ )環烷基或雜環基環稠合的6員芳族或5至6員雜芳環； Y為碳或氮； X為氫、鹵素、羥基、氰基或選自直鏈或分支鏈(C₁ -C₆ )烷基及(C₁ -C₆ )烷氧基之視情況經取代之基團；及 R5及R6獨立地為氫或選自以下之視情況經取代之基團：直鏈或分支鏈(C₁ -C₆ )烷基、(C₃ -C₆ )環烷基、雜環基、芳基及雜芳基。Other examples of other RET kinase inhibitors include the inhibitors described in International Publication No. WO 2016075224, which is incorporated herein by reference. For example, in some embodiments, the other RET inhibitor is a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein:

R1 and R2 are independently hydrogen or an optionally substituted group selected from the group consisting of linear or branched (C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl, and COR', wherein R' is an optionally substituted group selected from linear or branched (C ₁ -C ₆ )alkyl and (C ₃ -C ₆ )cycloalkyl; R3 is hydrogen or an optionally substituted group selected from Substituted groups: straight or branched (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, (C ₃ -C ₆ ) cycloalkyl , aryl, heteroaryl and 3 to 7 membered heterocyclyl rings; R4 is hydrogen or an optionally substituted group selected from the following: straight or branched (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, aryl, heteroaryl or heterocyclic group; A is a 5- or 6-membered heteroaryl ring or a benzene ring; B is selected from heteroaryl, (C ₅ -C ₆ ) cycloalkane 5- or 6-membered rings of radicals and heterocyclyl rings or benzene rings; wherein ring A and ring B are fused together to form a bicyclic ring system, which includes a 6-membered aromatic or 5 to 6-membered heteroaromatic, (C ₅ -C ₆ ) 6-membered aromatic or 5 to 6-membered heteroaromatic ring fused by cycloalkyl or heterocyclyl ring; Y is carbon or nitrogen; X is hydrogen, halogen, hydroxyl, cyano or selected from straight chain or Optionally substituted groups of branched chain (C ₁ -C ₆ )alkyl and (C ₁ -C ₆ )alkoxy groups; and R5 and R6 are independently hydrogen or optionally substituted groups selected from Group: linear or branched (C ₁ -C ₆ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, heterocyclic, aryl and heteroaryl.

X為NH、NR_x 、O或S，其中R_x 為(1-3C)烷基； R₁ 選自鹵基(例如氟、氯或溴)、三氟甲基、(1-4C)烷基(例如甲基)、(1-4C)烷氧基或(3-6C)環烷基，其中烷基、烷氧基或環烷基視情況經一或多個氟取代； R₂ 選自氫、鹵基(例如氟、氯或溴)、羥基、氰基、三氟甲基、三氟甲氧基、(1-6C)烷基(例如甲基)、(3-8C)環烷基或(1-4C)烷氧基(例如OMe)，其中烷基、環烷基或烷氧基視情況經一或多個氟取代； R₃ 選自氫、鹵基(例如氟、氯或溴)、羥基、氰基、三氟甲基、三氟甲氧基、(1-6C)烷基(例如甲基)、(3-8C)環烷基或(1-4C)烷氧基(例如OMe)，其中烷基、環烷基或烷氧基視情況經一或多個氟取代； R₄ 選自氫、鹵基(例如氟、氯或溴)、羥基、氰基、三氟甲基、三氟甲氧基、(1-6C)烷基(例如甲基)、(3-8C)環烷基或(1-4C)烷氧基(例如OMe)，其中烷基、環烷基或烷氧基視情況經一或多個氟取代； R₅ 選自氫或由下式定義之基團： -O-L₅ -X₅ -Q₅ ； 其中 L₅ 不存在或為直鏈或分支鏈(1-4C)伸烷基； X₅ 不存在或為-C(O)O-、-O-、-C(O)-、-OC(O)-、-CH(QR_5L )-、-N(R^j )-、-N(R_5L )-C(O)-、-N(R_5L )-C(O)O-、-C(O)-N(R_5L )-、-S-、-SO-、-SO₂ -、-S(O)₂ N(R_5L )-或-N(R_5L )SO₂ -，其中R_5L 選自氫或甲基；及 Q₅ 為(1-6C)烷基、(2-6C)烯基、(2-6C)炔基、(3-8C)環烷基、(3-8C)環烷基-(1-4C)烷基、芳基、芳基-(1-4C)烷基、雜芳基、雜芳基-(1-4C)烷基、雜環基或雜環基-(1-4C)烷基； R₆ 選自氫或由下式定義之基團： -O-L₆ -X₆ -Q₆ 其中 L₆ 不存在或為直鏈或分支鏈(1-4C)伸烷基； X₆ 不存在或選自-O-、-C(O)-、-C(O)O-、-OC(O)-、-CH(OR_6L )-、-N(R_6L )、-N(R_6L )-C(O)-、-N(R_6L )-C(O)O-、-C(O)-N(R_6L )-、-S-、-SO-、-SO₂ -、-S(O)₂ N(R_6L )-或-N(R_6L )SO₂ -，其中R_6L 選自氫或(1-3C)烷基； Q₆ 為氫、(1-8C)烷基、(2-8C)烯基、(2-8C)炔基、(3-8C)環烷基、(3-8C)環烷基-(1-6C)烷基、芳基、芳基-(1-6C)烷基、雜芳基、雜芳基-(1-6C)烷基、雜環基、雜環基-(1-6C)烷基， 或Q₆ 與R_L6 連接，使得其與其所連接之氮原子共同形成雜環； 其中R₆ 視情況經以下取代(例如在L₆ 及/或Q₆ 上取代)：一或多個(1-6C)烷基、(1-6C)烷醯基、OR_6X 、SR_6X 、S(O)R_6X 、S(O)₂ R_6X 、C(O)OR_6X 或C(O)NR_6X R'_6X ，其中R_6X 及R'_6X 獨立地為氫、(1-8C)烷基，或R_6X 與R'_6X 連接，使得其與其所連接之氮原子共同形成雜環；及 R₇ 選自氫、(1-6C)烷氧基，或由下式定義之基團： -O-L₇ -X₇ -Q₇ - 其中 L₇ 不存在或為直鏈或分支鏈(1-4C)伸烷基； X₇ 不存在或選自-O-、-C(O)-、-C(O)O-、-OC(O)-、-CH(OR_6L )-、-N(R_7L )-、-N(R_7L )-C(O)-、-N(R_7L )-C(O)O-、-C(O)-N(R_7L )-、-S-、-SO-、-SO₂ -、-S(O)₂ N(R_7L )-或-N(R_7L )SO₂ -，其中R_7L 選自氫或(1-3C)烷基； Q₇ 為氫、(1-8C)烷基、(2-8C)烯基、(2-8C)炔基、(3-8C)環烷基、(3-8C)環烷基-(1-6C)烷基、芳基、芳基-(1-6C)烷基、雜芳基、雜芳基-(1-6C)烷基、雜環基、雜環基-(1-6C)烷基， 或Q₇ 與R_7L 連接，使得其與其所連接之氮原子共同形成雜環； 其中R₇ 視情況經以下取代(例如在L₇ 及/或Q₇ 上取代)：一或多個鹵基、羥基、硝基、氰基、(1-8C)烷基、(1-8C)烷醯基、OR_7X 、SR_7X 、S(O)R_7X 、S(O)₂ R_7X 、C(O)OR_7X 或C(O)NR_7X R'_7X ，其中R_7X 及R'_7X 獨立地為氫、(1-8C)烷基，或R_7X 與R'_7X 連接，使得其與其所連接之氮原子共同形成雜環；或 R₇ 視情況經一或多個選自以下之基團取代：側氧基、(1-4C)鹵烷基、(1-4C)羥基烷基、C(O)R_7y 或NR_7y R'_7y ，其中R_7y 及R'_7y 獨立地為氫或(1-8C)烷基。Other examples of other RET kinase inhibitors include the inhibitors described in International Publication No. WO 2015079251, which is incorporated herein by reference. For example, in some embodiments, the other RET inhibitor is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein:

X is NH, _NRx , O or S, wherein _Rx is (1-3C)alkyl; _R1 is selected from halo (such as fluorine, chlorine or bromine), trifluoromethyl, (1-4C)alkyl (e.g. methyl), (1-4C) alkoxy or (3-6C) cycloalkyl, wherein the alkyl, alkoxy or cycloalkyl is optionally substituted by one or more fluorine; R _is selected from hydrogen , halo (such as fluorine, chlorine or bromine), hydroxyl, cyano, trifluoromethyl, trifluoromethoxy, (1-6C) alkyl (such as methyl), (3-8C) cycloalkyl or (1-4C) alkoxy (eg OMe), wherein alkyl, cycloalkyl or alkoxy is optionally substituted by one or more fluorine; _R is selected from hydrogen, halo (eg fluorine, chlorine or bromine) , hydroxy, cyano, trifluoromethyl, trifluoromethoxy, (1-6C) alkyl (such as methyl), (3-8C) cycloalkyl or (1-4C) alkoxy (such as OMe ), wherein the alkyl, cycloalkyl or alkoxy groups are optionally substituted by one or more fluorines; _R is selected from the group consisting of hydrogen, halo (such as fluorine, chlorine or bromine), hydroxyl, cyano, trifluoromethyl, Trifluoromethoxy, (1-6C) alkyl (such as methyl), (3-8C) cycloalkyl or (1-4C) alkoxy (such as OMe), wherein alkyl, cycloalkyl or alkane Oxygen is optionally substituted by one or more fluorines; _R is selected from hydrogen or a group defined by the following formula: -OL ₅ -X ₅ -Q ₅ ; wherein L ₅ does not exist or is a straight or branched chain (1 -4C) alkylene; X ₅ does not exist or is -C(O)O-, -O-, -C(O)-, -OC(O)-, -CH(QR _5L )-, -N( R ^j )-, -N(R _5L )-C(O)-, -N(R _5L )-C(O)O-, -C(O)-N(R _5L )-, -S-, - SO-, -SO ₂ -, -S(O) ₂ N(R _5L )- or -N(R _5L )SO ₂ -, wherein R _5L is selected from hydrogen or methyl; and Q ₅ is (1-6C) Alkyl, (2-6C) alkenyl, (2-6C) alkynyl, (3-8C) cycloalkyl, (3-8C) cycloalkyl-(1-4C) alkyl, aryl, aryl -(1-4C) alkyl, heteroaryl, heteroaryl-(1-4C) alkyl, heterocyclyl or heterocyclyl-(1-4C) alkyl; _R is selected from hydrogen or by the following formula Defined groups: -OL ₆ -X ₆ -Q ₆ wherein L ₆ does not exist or is a linear or branched (1-4C) alkylene group; X ₆ does not exist or is selected from -O-, -C(O )-, -C(O)O-, -OC(O)-, -CH(OR _6L )-, -N(R _6L ), -N(R _6L )-C(O)-, -N(R _6L )-C(O)O-, -C(O)-N(R _6L )-, -S-, -SO-, -SO ₂ -, -S(O) ₂ N(R _6L )- or - N(R _6L )SO ₂ -, wherein R _6L is selected from hydrogen or (1-3C) alkyl; Q ₆ is hydrogen, (1-8C) alkyl, (2-8C) alkenyl, (2-8C) Alkynyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl-(1-6C)alkyl, aryl, aryl-(1-6C)alkyl, heteroaryl, heteroaryl -(1-6C) alkyl, heterocyclyl, heterocyclyl-(1-6C) alkyl, or Q ₆ is connected with R _{L 6} so that it forms a heterocyclic ring with the nitrogen atom it is connected to; wherein R ₆ depends on In case substituted (for example on L ₆ and/or Q ₆ ): one or more (1-6C)alkyl, (1-6C)alkanyl, OR _6X , SR _6X , S(O)R _6X , S(O) ₂ R _6X , C(O)OR _6X or C(O)NR _6X R' _6X , wherein R _6X and R' _6X are independently hydrogen, (1-8C) alkyl, or R _6X is attached to R' _6X such that it forms a heterocyclic ring together with the nitrogen atom to which it is attached; and R ₇ is selected from hydrogen, (1-6C)alkoxy, or a group defined by the formula: -OL ₇ -X ₇ -Q ₇ -wherein L ₇ does not exist or is straight or branched (1-4C) alkylene; X ₇ does not exist or is selected from -O-, -C(O)-, -C(O)O- , -OC(O)-, -CH(OR _6L )-, -N(R _7L )-, -N(R _7L )-C(O)-, -N(R _7L )-C(O)O- , -C(O)-N(R _7L )-, -S-, -SO-, -SO ₂ -, -S(O) ₂ N(R _7L )- or -N(R _7L )SO ₂ -, Wherein R _7L is selected from hydrogen or (1-3C) alkyl; Q ₇ is hydrogen, (1-8C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl, (3-8C) ring Alkyl, (3-8C)cycloalkyl-(1-6C)alkyl, aryl, aryl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl, Heterocyclyl, heterocyclyl-(1-6C) alkyl, or Q ₇ is connected with R _7L such that it forms a heterocyclic ring with the nitrogen atom to which it is attached; wherein R ₇ is optionally substituted by the following (for example at L ₇ and/or substitution on Q ₇ ): one or more halo, hydroxyl, nitro, cyano, (1-8C) alkyl, (1-8C) alkyl, OR _7X , SR _7X , S(O )R _7X , S(O) ₂ R _7X , C(O)OR _7X or C(O)NR _7X R' _7X , wherein R _7X and R' _7X are independently hydrogen, (1-8C) alkyl, or R _7X is attached to R' _7X such that it forms a heterocyclic ring together with the nitrogen atom to which it is attached; or R ₇ is optionally substituted with one or more groups selected from the group consisting of pendant oxy, (1-4C) haloalkane radical, (1-4C) hydroxyalkyl, C(O)R _7y or NR _7y R' _7y , wherein R _7y and R' _7y are independently hydrogen or (1-8C) alkyl.

HET選自以下中之一者：

其中

表示連接點； R₁ 選自氫、(1-4C)鹵烷基、(1-4C)鹵烷氧基或下式之基團： -L-Y-Q 其中： L不存在或為(1-5C)伸烷基，其視情況經一或多個選自(1-2C)烷基或側氧基之取代基取代； Y不存在或為O、S、SO、SO₂ 、N(R_a )、C(O)、C(O)O、OC(O)、C(O)N(R_a )、N(R_a )C(O)、N(R_a )C(O)N(R_b )、N(R_a )C(O)O、OC(O)N(R_a )、S(O)₂ N(R_a )或N(R_a )SO₂ ，其中R_a 及R_b 各自獨立地選自氫或(1-4C)烷基；及 Q為氫、(1-6C)烷基、(2-6C)烯基、(2-6C)炔基、芳基、(3-10C)環烷基、(3-10C)環烯基、雜芳基或雜環基；其中Q視情況進一步經一或多個獨立地選自以下之取代基取代：(1-4C)烷基、鹵基、(1-4C)鹵烷基、(1-4C)鹵烷氧基、胺基、(1-4C)胺基烷基、氰基、羥基、羧基、胺甲醯基、胺磺醯基、巰基、脲基、NR_c R_d 、OR_c 、C(O)R_c 、C(O)OR_c 、OC(O)R_c 、C(O)N(R_d )R_c 、N(R_d )C(O)R_c 、S(O)_p R_c (其中p為0、1或2)、SO₂ N(R_d )R_c 、N(R_d )SO₂ R_c 、Si(Re)(R_d )R_c 或(CH₂ )_q NR_c R_d (其中q為1、2或3)；其中R_c 、R_d 及R_e 各自獨立地選自氫、(1-6C)烷基或(3-6C)環烷基；或R_c 與R_d 連接，其與其所連接之氮原子共同形成視情況經一或多個選自以下之取代基取代的4-7員雜環：(1-4C)烷基、鹵基、(1-4C)鹵烷基、(1-4C)鹵烷氧基、(1-4C)烷氧基、(1-4C)烷基胺基、胺基、氰基或羥基；或 Q視情況經下式之基團取代： -L₁ -L_Q1 -W₁ 其中： L₁ 不存在或為(1-3C)伸烷基，其視情況經一或多個選自(1-2C)烷基或側氧基之取代基取代； L_Q1 不存在或選自O、S、SO、SO₂ 、N(R_f )、C(O)、C(O)O、OC(O)、C(O)N(R_f )、N(R_f )C(O)、N(R_f )C(O)N(R_g )、N(R_f )C(O)O、OC(O)N(R_f )、S(O)₂ N(R_f )，或N(R_f )SO₂ ，其中R_f 及R_g 各自獨立地選自氫或(1-2C)烷基；及 W₁ 為氫、(1-6C)烷基、芳基、芳基(1-2C)烷基、(3-8C)環烷基、(3-8C)環烯基、雜芳基或雜環基；其中W₁ 視情況經一或多個選自以下之取代基取代：(1-4C)烷基、鹵基、(1-4C)鹵烷基、(1-4C)鹵烷氧基、(1-4C)烷氧基、(1-4C)烷基胺基、胺基、氰基、羥基、羧基、胺甲醯基、胺磺醯基、巰基、脲基、芳基、雜芳基、雜環基、(3-6C)環烷基、NR_h R_i 、OR_h 、C(O)R_h 、C(O)OR_h 、OC(O)R_h 、C(O)N(R_i )R_h 、N(R_i )C(O)R_h 、S(O)_r R_h (其中r為0、1或2)、SO₂ N(R_i )R_h 、N(R_i )SO₂ R_h 或(CH₂ )_s NR_i R_h (其中s為1、2或3)；其中R_h 及R_i 各自獨立地選自氫、(1-4C)烷基或(3-6C)環烷基； R_1a 及R_1b 係各自選自H、(1-4C)烷基、鹵基、(1-4C)鹵烷基、(1-4C)鹵烷氧基、(1-4C)烷氧基、(1-4C)烷基胺基、胺基、氰基、羥基、羧基、胺甲醯基、胺磺醯基或巰基； W選自O、S或NR_W1 ，其中R_W1 選自H或(1-2C)烷基； X₁ 、X₂ 、X₃ 及X₄ 係獨立地選自CH、CR₂ 或N； R₂ 選自氫、鹵基、(1-4C)烷基、(1-4C)烷氧基、(1-4C)鹵烷基、(1-4C)鹵烷氧基、胺基、氰基、硝基、芳基、雜芳基、雜環基、環烷基、(2-4C)炔基、NR_j R_k 、OR_j 、C(O)R_j 、C(O)OR_j 、OC(O)R_j 、C(O)N(R_k )R_j 、N(R_k )C(O)R_j 、N(R_k )C(O)N(R_j )、S(O)_r1 R_k (其中r₁ 為0、1或2)、SO₂ N(R_j )R_k 、N(R_j )SO₂ R_k 或(CH₂ )_v NR_j R_k (其中v為1、2或3)；其中R_j 及R_k 各自獨立地選自氫或(1-4C)烷基；且其中該(1-4C)烷基、芳基、雜芳基、雜環基或環烷基視情況經一或多個選自以下之取代基取代：鹵基、(1-4C)烷基、(1-4C)烷氧基、(1-4C)鹵烷基、(1-4C)鹵烷氧基、胺基、氰基、硝基、苯基、(2-4C)炔基、NR_j1 R_k1 、OR_j1 、C(O)R_j1 、C(O)OR_j1 、OC(O)R_j1 、C(O)N(R_k1 )R_j1 、N(R_k1 )C(O)R_j1 、S(O)_r2 R_h (其中r₂ 為0、1或2)、SO₂ N(R_j1 )R_k1 、N(R_j1 )SO₂ R_k1 或(CH₂ )_v1 NR_j1 R_k1 (其中v₁ 為1、2或3)；且其中R_j1 及R_k1 各自獨立地選自氫或(1-4C)烷基；及 R₃ 選自鹵基、(1-4C)烷基、(1-4C)烷氧基、(1-4C)鹵烷基、(1-4C)鹵烷氧基、胺基、氰基、硝基、(2-4C)炔基、NR_l R_m 、OR_l 、C(O)R_l 、C(O)OR_l 、OC(O)R_l 、C(O)N(R_m )R_l 、N(R_m )C(O)R_l 或(CH₂ )_y NR_l R_m (其中y為1、2或3)；其中該(1-4C)烷基視情況經一或多個選自胺基、羥基、(1-2C)烷氧基或鹵基之取代基取代；且其中R_l 及R_m 各自獨立地選自氫或(1-4C)烷基。Other examples of other RET kinase inhibitors include the inhibitors described in International Publication No. WO2017178845, which is incorporated herein by reference. For example, in some embodiments, the other RET inhibitor is a compound of formula (IV) or a pharmaceutically acceptable salt thereof, wherein:

HET is selected from one of the following:

in

Indicates the connection point; R ₁ is selected from hydrogen, (1-4C) haloalkyl, (1-4C) haloalkoxy or a group of the following formula: -LYQ wherein: L does not exist or is (1-5C) Alkyl, which is optionally substituted by one or more substituents selected from (1-2C)alkyl or pendant oxy; Y is absent or is O, S, SO, SO ₂ , N(R _a ), C (O), C(O)O, OC(O), C(O)N(R _a ), N(R _a )C(O), N(R _a )C(O)N(R _b ), N(R _a )C(O)O, OC(O)N(R _a ), S(O) ₂ N(R _a ) or N(R _a )SO ₂ , wherein R _a and R _b are each independently selected from From hydrogen or (1-4C) alkyl; and Q is hydrogen, (1-6C) alkyl, (2-6C) alkenyl, (2-6C) alkynyl, aryl, (3-10C) cycloalkane radical, (3-10C)cycloalkenyl, heteroaryl or heterocyclyl; where Q is optionally further substituted by one or more substituents independently selected from the following: (1-4C)alkyl, halo, (1-4C) haloalkyl, (1-4C) haloalkoxy, amino, (1-4C) aminoalkyl, cyano, hydroxyl, carboxyl, carbamoyl, sulfamoyl, mercapto , ureido, NR _c R _d , OR _c , C(O)R _c , C(O)OR _c , OC(O)R _c , C(O)N(R _d )R _c , N(R _d ) C(O)R _c , S(O) _p R _c (where p is 0, 1 or 2), SO ₂ N(R _d )R _c , N(R _d )SO ₂ R _c , Si(Re)( R _d ) R _c or (CH ₂ ) _q NR _c R _d (wherein q is 1, 2 or 3); wherein R _c , R _d and _Re are each independently selected from hydrogen, (1-6C) alkyl or (3-6C) cycloalkyl; or R _c is connected to R _d , which together with the nitrogen atom to which it is connected forms a 4-7 membered heterocyclic ring optionally substituted by one or more substituents selected from the group consisting of: (1 -4C) alkyl, halo, (1-4C) haloalkyl, (1-4C) haloalkoxy, (1-4C) alkoxy, (1-4C) alkylamino, amino, A cyano group or a hydroxyl group; or Q is optionally substituted by a group of the following formula: -L ₁ -L _Q1 -W ₁ wherein: L ₁ is absent or is (1-3C)alkylene, which is optionally substituted by one or more Substituents selected from (1-2C) alkyl or side oxygen; L _Q1 does not exist or is selected from O, S, SO, SO ₂ , N(R _f ), C(O), C(O) O, OC(O), C(O)N(R _f ), N(R _f )C(O), N(R _f )C(O)N(R _g ), N(R _f )C(O )O, OC(O)N( _Rf ), S(O) _2N ( _Rf ), or N( _Rf ) _SO2 , wherein _Rf and _Rg are each independently selected from hydrogen or (1-2C ) alkyl; and W _is hydrogen, (1-6C) alkyl, aryl, aryl (1-2C) alkyl, (3-8C) cycloalkyl, (3-8C) cycloalkenyl, hetero Aryl or heterocyclyl; wherein _W is optionally substituted by one or more substituents selected from the following: (1-4C) alkyl, halo, (1-4C) haloalkyl, (1-4C) Haloalkoxy, (1-4C) alkoxy, (1-4C) alkylamino, amine, cyano, hydroxyl, carboxyl, aminoformyl, sulfamoyl, mercapto, ureido, aromatic base, heteroaryl, heterocyclyl, (3-6C)cycloalkyl, NR _h R _i , OR _h , C(O)R _h , C(O)OR _h , OC(O)R _h , C( O)N(R _i )R _h , N(R _i )C(O)R _h , S(O) _r R _h (where r is 0, 1 or 2), SO ₂ N(R _i )R _h , N(R _i )SO ₂ R _h or (CH ₂ ) _s NR _i R _h (wherein s is 1, 2 or 3); wherein R _h and R _i are each independently selected from hydrogen, (1-4C) alkyl Or (3-6C) cycloalkyl; R _1a and R _1b are each selected from H, (1-4C) alkyl, halo, (1-4C) haloalkyl, (1-4C) haloalkoxy , (1-4C) alkoxyl group, (1-4C) alkylamino group, amine group, cyano group, hydroxyl group, carboxyl group, aminoformyl group, sulfamoyl group or mercapto group; W is selected from O, S or NR _W1 , wherein R _W1 is selected from H or (1-2C) alkyl; X ₁ , X ₂ , X ₃ and X ₄ are independently selected from CH, CR ₂ or N; R ₂ is selected from hydrogen, halo, ( 1-4C) alkyl, (1-4C) alkoxy, (1-4C) haloalkyl, (1-4C) haloalkoxy, amino, cyano, nitro, aryl, heteroaryl , heterocyclyl, cycloalkyl, (2-4C)alkynyl, NR _j R _k , OR _j , C(O)R j , C(O)OR _j , OC(O ₎ R _j , C(O) N(R _k )R _j , N(R _k )C(O)R _j , N(R _k )C(O)N(R _j ), S(O) _r1 R _k (where r ₁ is 0, 1 or 2), SO ₂ N(R _j )R _k , N(R _j )SO ₂ R _k or (CH ₂ ) _v NR _j R _k (where v is 1, 2 or 3); where R _j and R _k each independently selected from hydrogen or (1-4C) alkyl; and wherein the (1-4C) alkyl, aryl, heteroaryl, heterocyclyl or cycloalkyl is optionally selected from one or more of the following Substituent substitution: halo, (1-4C) alkyl, (1-4C) alkoxy, (1-4C) haloalkyl, (1-4C) haloalkoxy, amino, cyano, Nitro, phenyl, (2-4C)alkynyl, NR _j1 R _k1 , OR _j1 , C(O)R _j1 , C(O)OR _j1 , OC(O)R _j1 , C(O)N(R _k1 )R _j1 , N(R _k1 )C(O)R _j1 , S(O) _r2 R _h (where r ₂ is 0, 1 or 2), SO ₂ N(R _j1 )R _k1 , N(R _j1 ) SO ₂ R _k1 or (CH ₂ ) _v1 NR _j1 R _k1 (where v ₁ is 1, 2 or 3); and wherein R _j1 and R _k1 are each independently selected from hydrogen or (1-4C)alkyl; and R ₃ is selected from halo, (1-4C) alkyl, (1-4C) alkoxy, (1-4C) haloalkyl, (1-4C) haloalkoxy, amino, cyano, nitro base, (2-4C)alkynyl, NR _l R _m , OR _l , C(O)R _l , C(O)OR _l , OC(O)R _l , C(O)N(R _m )R _l , N(R _m )C(O)R _l or (CH ₂ ) _y NR _l R _m (wherein y is 1, 2 or 3); wherein the (1-4C) alkyl is optionally selected from one or more Substituents from amino, hydroxyl, (1-2C) alkoxy or halo; and wherein R ₁ and R _m are each independently selected from hydrogen or (1-4C) alkyl.

HET選自以下中之一者：

其中

表示連接點； R₁ 選自氫、(1-4C)鹵烷基、(1-4C)鹵烷氧基或下式之基團： -L-Y-Q 其中： L不存在或為(1-5C)伸烷基，其視情況經一或多個選自(1-2C)烷基或側氧基之取代基取代； Y不存在或為O、S、SO、SO₂ 、N(R_a )、C(O)、C(O)O、OC(O)、C(O)N(R_a )、N(R_a )C(O)、N(R_a )C(O)N(R_b )、N(R_a )C(O)O、OC(O)N(R_a )、S(O)₂ N(R_a )或N(R_a )SO₂ ，其中R_a 及R_b 各自獨立地選自氫或(1-4C)烷基；及 Q為氫、(1-6C)烷基、(2-6C)烯基、(2-6C)炔基、芳基、(3-10C)環烷基、(3-10C)環烯基、雜芳基或雜環基；其中Q視情況進一步經一或多個獨立地選自以下之取代基取代：(1-4C)烷基、鹵基、(1-4C)鹵烷基、(1-4C)鹵烷氧基、胺基、(1-4C)胺基烷基、氰基、羥基、羧基、胺甲醯基、胺磺醯基、巰基、脲基、NR_c R_d 、OR_c 、C(O)R_c 、C(O)OR_c 、OC(O)R_c 、C(O)N(R_d )R_c 、N(R_d )C(O)R_c 、S(O)_y R_c (其中y為0、1或2)、SO₂ N(R_d )R_c 、N(R_d )SO₂ R_c 、Si(R_d )(R_c )R_e 或(CH₂ )_z NR_c R_d (其中z為1、2或3)；其中R_c 、R_d 及R_e 各自獨立地選自氫、(1-6C)烷基或(3-6C)環烷基；或R_c 與R_d 可連接，使得其與其所連接之氮原子共同形成視情況經一或多個選自以下之取代基取代的4-7員雜環：(1-4C)烷基、鹵基、(1-4C)鹵烷基、(1-4C)鹵烷氧基、(1-4C)烷氧基、(1-4C)烷基胺基、胺基、氰基或羥基；或 Q視情況經下式之基團取代： -L₁ -L_Q1 -Z₁ 其中： L₁ 不存在或為(1-3C)伸烷基，其視情況經一或多個選自(1-2C)烷基或側氧基之取代基取代； L_Q1 不存在或選自O、S、SO、SO₂ 、N(R_f )、C(O)、C(O)O、OC(O)、C(O)N(R_f )、N(R_f )C(O)、N(R_g )C(O)N(R_f )、N(R_f )C(O)O、OC(O)N(R_f )、S(O)₂ N(R_f )，或N(R_f )SO₂ ，其中R_f 及R_g 各自獨立地選自氫或(1-2C)烷基；及 Z₁ 為氫、(1-6C)烷基、芳基、芳基(1-2C)烷基、(3-8C)環烷基、(3-8C)環烯基、雜芳基或雜環基；其中Z₁ 視情況經一或多個選自以下之取代基取代：(1-4C)烷基、鹵基、(1-4C)鹵烷基、(1-4C)鹵烷氧基、(1-4C)烷氧基、(1-4C)烷基胺基、胺基、氰基、羥基、羧基、胺甲醯基、胺磺醯基、巰基、脲基、芳基、雜芳基、雜環基、(3-6C)環烷基、NR_h R_i 、OR_h 、C(O)R_h 、C(O)OR_h 、OC(O)R_h 、C(O)N(R_i )R_h 、N(R_i )C(O)R_h 、S(O)_ya R_h (其中y^a 為0、1或2)、SO₂ N(R_i )R_h 、N(R_i )SO₂ R_h 或(CH₂ )_za NR_i R_h (其中z^a 為1、2或3)；其中R_h 及R_i 各自獨立地選自氫、(1-4C)烷基或(3-6C)環烷基； R_1a 及R_1b 係各自選自氫、(1-4C)烷基、鹵基、(1-4C)鹵烷基、(1-4C)鹵烷氧基、(1-4C)烷氧基、(1-4C)烷基胺基、胺基、氰基、羥基、羧基、胺甲醯基、胺磺醯基或巰基； W選自O、S或NR_j ，其中R_j 選自H或(1-2C)烷基； X₁ 及X₂ 係各自獨立地選自N或CR_k ； 其中 R_k 選自氫、鹵基、(1-4C)烷基、(1-4C)烷氧基、胺基、(1-4C)烷基胺基、(1-4C)二烷基胺基、氰基、(2C)炔基、C(O)R_k1 、C(O)OR_k1 、OC(O)R_k1 、C(O)N(R_k2 )R_k1 、N(R_k2 )C(O)R_k1 、S(O)_yb R_k1 (其中y^b 為0、1或2)、SO₂ N(R_k2 )R_k1 、N(R_k2 )SO₂ R_k1 或(CH₂ )_zb NR_k1 R_k2 (其中z^b 為1、2或3)；其中該(1-4C)烷基視情況經一或多個選自胺基、羥基、(1-2C)烷氧基或鹵基之取代基取代；及 R_k1 及R_k2 係各自獨立地選自氫或(1-4C)烷基； X₃ 選自N或CR_m ； 其中 R_m 選自氫、鹵基、(1-4C)烷基、(1-4C)烷氧基、胺基、(1-4C)烷基胺基、(1-4C)二烷基胺基、氰基、(2C)炔基、C(O)R_m1 、C(O)OR_m1 、OC(O)R_m1 、C(O)N(R_m2 )R_m1 、N(R_m2 )C(O)R_m1 、S(O)_yc R_m1 (其中y^c 為0、1或2)、SO₂ N(R_m2 )R_m1 、N(R_m2 )SO₂ R_m1 或(CH₂ )_zc NR_m1 R_m2 (其中zc為1、2或3)；其中該(1-4C)烷基視情況經一或多個選自胺基、羥基、(1-2C)烷氧基或鹵基之取代基取代；及 R_m1 及R_m2 係各自獨立地選自氫或(1-4C)烷基； R_o 選自鹵基、(1-4C)烷基、(1-4C)烷氧基、胺基、(1-4C)烷基胺基、(1-4C)二烷基胺基、氰基、(2C)炔基、C(O)R_o1 、C(O)OR_o1 、OC(O)R_o1 、C(O)N(R_o2 )R_o1 、N(R_o2 )C(O)R_o1 、S(O)_yd R_o1 (其中y^d 為0、1或2)、SO₂ N(R_o2 )R_o1 、N(R_o2 )SO₂ R_o1 或(CH₂ )_zd NR_o1 R_o2 (其中z^d 為1、2或3)；其中該(1-4C)烷基視情況經一或多個選自胺基、羥基、(1-2C)烷氧基或鹵基之取代基取代；及 R_o1 及R_o2 係各自獨立地選自氫或(1-4C)烷基； R₂ 選自氫、(1-4C)烷基或下式之基團： -L₂ -Y₂ -Q₂ 其中： L₂ 不存在或為視情況經一或多個選自(1-2C)烷基或側氧基之取代基取代之(1-3C)伸烷基； Y₂ 不存在或為C(O)、C(O)O、C(O)N(R_p )，其中R_p 選自氫或(1-4C)烷基；及 Q₂ 為氫、(1-6C)烷基、芳基、(3-8C)環烷基、(3-8C)環烯基、雜芳基或雜環基；其中Q₂ 視情況進一步經一或多個獨立地選自以下之取代基取代：(1-4C)烷基、鹵基、(1-4C)鹵烷基、(1-4C)鹵烷氧基、胺基、氰基、羥基、羧基、胺甲醯基、胺磺醯基、NR_q R_r 、OR_q ，其中R_q 及R_r 各自獨立地選自氫、(1-4C)烷基或(3-6C)環烷基； R₃ 選自下式之基團： -Y₃ -Q₃ 其中： Y₃ 為C(O)、C(O)N(R_y )、C(O)N(R_y )O、N(R_y )(O)C、C(O)O、OC(O)、N(R_y )C(O)N(R_y1 )、SO₂ N(R_y )、N(R_y )SO₂ 、噁唑基、三唑基、噁二唑基、噻唑基、咪唑基、噻二唑基、吡啶基、吡唑基、吡咯基或四唑基，其中R_y 及R_y1 獨立地選自氫或(1-2C)烷基；及 Q₃ 為氫、(1-6C)烷基、芳基、芳基(1-2C)烷基、(3-8C)環烷基、(3-8C)環烯基、雜芳基或雜環基；其中Q₃ 視情況進一步經一或多個獨立地選自以下之取代基取代：(1-4C)烷基、鹵基、(1-4C)鹵烷基、(1-4C)鹵烷氧基、胺基、氰基、羥基、羧基、胺甲醯基、胺磺醯基、NR_z R_aa 、OR_z ，其中R_z 及R_aa 各自獨立地選自氫、(1-4C)烷基或(3-6C)環烷基；或Q₃ 視情況經下式之基團取代： -L₄ -L_Q4 -Z₄ 其中： L₄ 不存在或為(1-3C)伸烷基，其視情況經一或多個選自(1-2C)烷基或側氧基之取代基取代； L_Q4 不存在或選自或為O、S、SO、SO₂ 、N(R_ab )、C(O)、C(O)O、OC(O)、C(O)N(R_ab )、N(R_ab )C(O)、N(R_ac )C(O)N(R_ab )、N(R_ab )C(O)O、OC(O)N(R_ab )、S(O)₂ N(R_ab )或N(R_ab )SO₂ ，其中R_ab 及R_ac 各自獨立地選自氫或(1-2C)烷基；及 Z₄ 為氫、(1-6C)烷基、芳基、芳基(1-2C)烷基、(3-8C)環烷基、(3-8C)環烯基、雜芳基或雜環基；其中Z₄ 視情況經一或多個選自以下之取代基取代：(1-4C)烷基、鹵基、(1-4C)鹵烷基、(1-4C)鹵烷氧基、(1-4C)烷氧基、(1-4C)烷基胺基、胺基、氰基、羥基、羧基、胺甲醯基、胺磺醯基、巰基、脲基、芳基、雜芳基、雜環基、(3-6C)環烷基、NR_ad R_ae 、OR_ad 、C(O)R_ad 、C(O)OR_ad 、OC(O)R_ad 、C(O)N(R_ae )R_ad 、N(R_ae )C(O)R_ad 、S(O)_ye R_ad (其中y^e 為0、1或2)、SO₂ N(R_ae )R_ad 、N(R_ae )SO₂ R_ad 或(CH₂ )_ze NR_ad R_ae (其中z^e 為1、2或3)；其中R_ad 及R_ae 各自獨立地選自氫、(1-4C)烷基或(3-6C)環烷基；或 Q₃ 與R_y 連接，使得其與其所連接之氮原子共同形成視情況經一或多個選自以下之取代基取代的4-7員雜環：(1-4C)烷基、鹵基、(1-4C)鹵烷基、(1-4C)鹵烷氧基、(1-4C)烷氧基、(1-4C)烷基胺基、胺基、氰基或羥基； 其限制條件為X₁ 、X₂ 或X₃ 中僅一或兩者可為N。Other examples of other RET kinase inhibitors include the inhibitors described in International Publication No. WO2017178844, which is incorporated herein by reference. For example, in some embodiments, the other RET inhibitor is a compound of formula (V) or a pharmaceutically acceptable salt thereof, wherein:

HET is selected from one of the following:

in

Indicates the connection point; R ₁ is selected from hydrogen, (1-4C) haloalkyl, (1-4C) haloalkoxy or a group of the following formula: -LYQ wherein: L does not exist or is (1-5C) Alkyl, which is optionally substituted by one or more substituents selected from (1-2C)alkyl or pendant oxy; Y is absent or is O, S, SO, SO ₂ , N(R _a ), C (O), C(O)O, OC(O), C(O)N(R _a ), N(R _a )C(O), N(R _a )C(O)N(R _b ), N(R _a )C(O)O, OC(O)N(R _a ), S(O) ₂ N(R _a ) or N(R _a )SO ₂ , wherein R _a and R _b are each independently selected from From hydrogen or (1-4C) alkyl; and Q is hydrogen, (1-6C) alkyl, (2-6C) alkenyl, (2-6C) alkynyl, aryl, (3-10C) cycloalkane radical, (3-10C)cycloalkenyl, heteroaryl or heterocyclyl; where Q is optionally further substituted by one or more substituents independently selected from the following: (1-4C)alkyl, halo, (1-4C) haloalkyl, (1-4C) haloalkoxy, amino, (1-4C) aminoalkyl, cyano, hydroxyl, carboxyl, carbamoyl, sulfamoyl, mercapto , ureido, NR _c R _d , OR _c , C(O)R _c , C(O)OR _c , OC(O)R _c , C(O)N(R _d )R _c , N(R _d ) C(O)R _c , S(O) _y R _c (where y is 0, 1 or 2), SO ₂ N(R _d )R _c , N(R _d )SO ₂ R _c , Si(R _d ) (R _c ) _Re or (CH ₂ ) _z NR _c R _d (wherein z is 1, 2 or 3); wherein R _c , R _d and _Re are each independently selected from hydrogen, (1-6C) alkyl or (3-6C)cycloalkyl; or R _c and R _d may be linked such that they form together with the nitrogen atom to which they are attached a 4-7 membered heterocyclic ring optionally substituted by one or more substituents selected from the following : (1-4C) alkyl, halo, (1-4C) haloalkyl, (1-4C) haloalkoxy, (1-4C) alkoxy, (1-4C) alkylamino, Amino, cyano or hydroxyl; or Q is optionally substituted by a group of the following formula: -L ₁ -L _Q1 -Z ₁ wherein: L ₁ is absent or is (1-3C)alkylene, which is optionally substituted by One or more substituents selected from (1-2C) alkyl or side oxy group are substituted; L _Q1 does not exist or is selected from O, S, SO, SO ₂ , N(R _f ), C(O), C (O)O, OC(O), C(O)N(R _f ), N(R _f )C(O), N(R _g )C(O)N(R _f ), N(R _f ) C(O)O, OC(O)N( _Rf ), S(O) _2N ( _Rf ), or N( _Rf ) _SO2 , wherein _Rf and _Rg are each independently selected from hydrogen or ( 1-2C) alkyl; and Z _is hydrogen, (1-6C) alkyl, aryl, aryl (1-2C) alkyl, (3-8C) cycloalkyl, (3-8C) cycloalkene radical, heteroaryl or heterocyclyl; wherein _Z is optionally substituted by one or more substituents selected from the group consisting of: (1-4C) alkyl, halo, (1-4C) haloalkyl, (1 -4C) haloalkoxy, (1-4C) alkoxy, (1-4C) alkylamino, amine, cyano, hydroxyl, carboxyl, carbamoyl, sulfamoyl, mercapto, urea radical, aryl, heteroaryl, heterocyclyl, (3-6C)cycloalkyl, NR _h R _i , OR _h , C(O)R _h , C(O)OR _h , OC(O)R _h , C(O)N(R _i )R _h , N(R _i )C(O)R _h , S(O) _ya R _h (where y ^a is 0, 1 or 2), SO ₂ N(R _i )R _h , N(R _i )SO ₂ R _h or (CH ₂ ) _za NR _i R _h (where z ^a is 1, 2 or 3); wherein R _h and R _i are each independently selected from hydrogen, (1 -4C) alkyl or (3-6C) cycloalkyl; R _1a and R _1b are each selected from hydrogen, (1-4C) alkyl, halo, (1-4C) haloalkyl, (1-4C ) haloalkoxy, (1-4C) alkoxy, (1-4C) alkylamino, amino, cyano, hydroxyl, carboxyl, carbamoyl, sulfamoyl or mercapto; W is selected from O, S or NR _j , wherein R _j is selected from H or (1-2C) alkyl; X ₁ and X ₂ are each independently selected from N or CR _k ; wherein R _k is selected from hydrogen, halo, (1 -4C) alkyl, (1-4C) alkoxy, amino, (1-4C) alkylamino, (1-4C) dialkylamino, cyano, (2C) alkynyl, C ( O)R _k1 , C(O)OR _k1 , OC(O)R _k1 , C(O)N(R _k2 )R _k1 , N(R _k2 )C(O)R _k1 , S(O) _yb R _k1 (where y ^b is 0, 1 or 2), SO ₂ N(R _k2 ) R _k1 , N(R _k2 )SO ₂ R _k1 or (CH ₂ ) _zb NR _k1 R _k2 (where z ^b is 1, 2 or 3); wherein the (1-4C) alkyl is optionally substituted by one or more substituents selected from amino, hydroxyl, (1-2C) alkoxy or halo; and R _k1 and R _k2 are each independently selected from hydrogen or (1-4C) alkyl; X ₃ is selected from N or CR _m ; wherein R _m is selected from hydrogen, halo, (1-4C) alkyl, (1-4C) alkoxy, Amino, (1-4C) alkylamino, (1-4C) dialkylamino, cyano, (2C) alkynyl, C(O)R _m1 , C(O)OR _m1 , OC(O )R _m1 , C(O)N(R _m2 )R _m1 , N(R _m2 )C(O)R _m1 , S(O) _yc R _m1 (where y ^c is 0, 1 or 2), SO ₂ N (R _m2 ) R _m1 , N(R _m2 ) SO ₂ R _m1 or (CH ₂ ) _zc NR _m1 R _m2 (wherein zc is 1, 2 or 3); wherein the (1-4C) alkyl is optionally treated with a or a plurality of substituents selected from amino, hydroxyl, (1-2C) alkoxy or halo; and R _m1 and R _m2 are each independently selected from hydrogen or (1-4C) alkyl; R _o Selected from halo, (1-4C) alkyl, (1-4C) alkoxy, amino, (1-4C) alkylamino, (1-4C) dialkylamino, cyano, ( 2C) Alkynyl, C(O)R _o1 , C(O)OR _o1 , OC(O)R _o1 , C(O)N(R _o2 )R _o1 , N(R _o2 )C(O)R _o1 , S(O) _yd R _o1 (where y ^d is 0, 1 or 2), SO ₂ N(R _o2 )R _o1 , N(R _o2 )SO ₂ R _o1 or (CH ₂ ) _zd NR _o1 R _o2 (where z ^d is 1, 2 or 3); wherein the (1-4C)alkyl is optionally substituted by one or more substituents selected from amino, hydroxyl, (1-2C)alkoxy or halo; and R _o1 and R _o2 are each independently selected from hydrogen or (1-4C) alkyl; R ₂ is selected from hydrogen, (1-4C) alkyl or a group of the following formula: -L ₂ -Y ₂ -Q ₂ Wherein: _L does not exist or is optionally substituted with one or more substituents selected from (1-2C) alkyl or side oxy (1-3C) alkylene; _Y does not exist or is C ( O), C(O)O, C(O)N( _Rp ), wherein _Rp is selected from hydrogen or (1-4C)alkyl; and _Q2 is hydrogen, (1-6C)alkyl, aryl , (3-8C) cycloalkyl, (3-8C) cycloalkenyl, heteroaryl or heterocyclyl; wherein Q ₂ is optionally further substituted by one or more substituents independently selected from the following: (1 -4C) alkyl, halo, (1-4C) haloalkyl, (1-4C) haloalkoxy, amine, cyano, hydroxyl, carboxyl, carbamoyl, sulfamoyl, NR _q R _r , OR _q , wherein R _q and R _r are each independently selected from hydrogen, (1-4C) alkyl or (3-6C) cycloalkyl; R ₃ is selected from groups of the following formula: -Y ₃ - Q ₃ where: Y ₃ is C(O), C(O)N(R _y ), C(O)N(R _y )O, N(R _y )(O)C, C(O)O, OC (O), N(R _y )C(O)N(R _y1 ), SO ₂ N(R _y ), N(R _y )SO ₂ , oxazolyl, triazolyl, oxadiazolyl, thiazolyl , imidazolyl, thiadiazolyl, pyridyl, pyrazolyl, pyrrolyl or tetrazolyl, wherein Ry _{and Ry1} are independently selected from hydrogen or (1-2C) alkyl; and _Q3 is hydrogen, ( 1-6C) alkyl, aryl, aryl (1-2C) alkyl, (3-8C) cycloalkyl, (3-8C) cycloalkenyl, heteroaryl or heterocyclyl; wherein Q ₃ depends on The case is further substituted with one or more substituents independently selected from: (1-4C) alkyl, halo, (1-4C) haloalkyl, (1-4C) haloalkoxy, amino, Cyano, hydroxyl, carboxyl, carbamoyl, sulfamoyl, NR _z R _aa , OR _z , wherein R _z and R _aa are each independently selected from hydrogen, (1-4C) alkyl or (3-6C ) cycloalkyl; or Q ₃ is optionally substituted by a group of the following formula: -L ₄ -L _Q4 -Z ₄ wherein: L ₄ is absent or is (1-3C)alkylene, which is optionally substituted by one or A plurality of substituents selected from (1-2C) alkyl or side oxygen are substituted; L _Q4 does not exist or is selected from or is O, S, SO, SO ₂ , N(R _ab ), C(O), C (O)O, OC(O), C(O)N(R _ab ), N(R _ab )C(O), N(R _ac )C(O)N(R _ab ), N(R _ab ) C(O)O, OC(O)N(R _ab ), S(O) ₂ N(R _ab ) or N(R _ab )SO ₂ , wherein R _ab and R _ac are each independently selected from hydrogen or (1 -2C) alkyl; and _Z4 is hydrogen, (1-6C) alkyl, aryl, aryl (1-2C) alkyl, (3-8C) cycloalkyl, (3-8C) cycloalkenyl , heteroaryl or heterocyclyl; wherein Z ₄ is optionally substituted by one or more substituents selected from: (1-4C) alkyl, halo, (1-4C) haloalkyl, (1- 4C) Haloalkoxy, (1-4C) alkoxy, (1-4C) alkylamino, amine, cyano, hydroxyl, carboxyl, carbamoyl, sulfamoyl, mercapto, ureido , aryl, heteroaryl, heterocyclyl, (3-6C)cycloalkyl, NR _{ad Rae} , OR _ad , C(O)Rad , C(O _{)OR ad ,} OC(O) _Rad , C(O)N(R _ae )R _ad , N(R _ae )C(O)R _ad , S(O) _ye R _ad (where y ^e is 0, 1 or 2), SO ₂ N(R _ae ) R _ad , N(R _ae )SO ₂ R _ad or (CH ₂ ) _ze NR _{ad Rae} (wherein z ^e is 1, 2 or 3); wherein R _ad and _Rae are each independently selected from hydrogen, (1- 4C) alkyl or (3-6C) cycloalkyl; or Q ₃ is connected to R _y such that it and the nitrogen atom to which it is connected together form 4-7 optionally substituted by one or more substituents selected from the following Member heterocycle: (1-4C) alkyl, halo, (1-4C) haloalkyl, (1-4C) haloalkoxy, (1-4C) alkoxy, (1-4C) alkyl Amino group, amino group, cyano group or hydroxyl group; the limitation is that only one or both of X ₁ , X ₂ or X ₃ can be N.

Other examples of other RET kinase inhibitors include the inhibitors described in International Publication No. WO 2017145050, which is incorporated herein by reference. For example, in some embodiments, the other RET has formula (VI) or a pharmaceutically acceptable salt thereof.

Other examples of other RET kinase inhibitors include the inhibitors described in International Publication No. WO 2016038552, which is incorporated herein by reference. For example, in some embodiments, the other RET is of formula (VII) or formula (VIII), or a pharmaceutically acceptable salt thereof.

其中： HET選自以下中之一者：

其中

表示連接點； R₁ 選自氫、(1-4C)鹵烷基、(1-4C)鹵烷氧基或下式之基團： -L-Y-Q 其中： L不存在或為(1-5C)伸烷基，其視情況經一或多個選自(1-2C)烷基或側氧基之取代基取代； Y不存在或為O、S、SO、SO₂ 、N(R_a )、C(O)、C(O)O、OC(O)、C(O)N(R_a )、N(R_a )C(O)、N(R_a )C(O)N(R_b )、N(R_a )C(O)O、OC(O)N(R_a )、S(O)₂ N(R_a )或N(R_a )SO₂ ，其中R_a 及R_b 各自獨立地選自氫或(1-4C)烷基；及 Q為氫、(1-6C)烷基、(2-6C)烯基、(2-6C)炔基、芳基、(3-10C)環烷基、(3-10C)環烯基、雜芳基或雜環基； 其中Q視情況進一步經一或多個獨立地選自以下之取代基取代：(1-4C)烷基、鹵基、(1-4C)鹵烷基、(1-4C)鹵烷氧基、胺基、(1-4C)胺基烷基、氰基、羥基、羧基、胺甲醯基、胺磺醯基、巰基、脲基、NR_c R_d 、OR_c 、C(O)R_c 、C(O)OR_c 、OC(O)R_c 、C(O)N(R_d )R_c 、N(R_d )C(O)R_c 、S(O)_y R_c (其中y為0、1或2)、SO₂ N(R_d )R_c 、N(R_d )SO₂ R_c 、Si(R_d )(R_c )R_e 或(CH₂ )_z NR_d R_c (其中z為1、2或3)；其中R_e 、R_d 及R_e 各自獨立地選自氫、(1-6C)烷基或(3-6C)環烷基；或R_c 可與R_d 連接，使得其與其所連接之氮原子共同形成4-7員雜環，其視情況經一或多個選自以下之取代基取代：(1-4C)烷基、鹵基、(1-4C)鹵烷基、(1-4C)鹵烷氧基、(1-4C)烷氧基、(1-4C)烷基胺基、胺基、氰基或羥基；或 Q視情況經下式之基團取代： -L₁ -L_Q1 -Z₁ 其中： L₁ 不存在或為(1-3C)伸烷基，其視情況經一或多個選自(1-2C)烷基或側氧基之取代基取代； L_Q1 不存在或選自或為O、S、SO、SO₂ 、N(R_f )、C(O)、C(O)O、OC(O)、C(O)N(R_f )、N(R_f )C(O)、N(R_g )C(O)N(R_f )、N(R_f )C(O)O、OC(O)N(R_f )、S(O)₂ N(R_f )或N(R_f )SO₂ ，其中R_f 及R_g 各自獨立地選自氫或(1-2C)烷基；及 Z₁ 為氫、(1-6C)烷基、芳基、芳基(1-2C)烷基、(3-8C)環烷基、(3-8C)環烯基、雜芳基或雜環基；其中Z₁ 視情況經一或多個選自以下之取代基取代：(1-4C)烷基、鹵基、(1-4C)鹵烷基、(1-4C)鹵烷氧基、(1-4C)烷氧基、(1-4C)烷基胺基、胺基、氰基、羥基、羧基、胺甲醯基、胺磺醯基、巰基、脲基、芳基、雜芳基、雜環基、(3-6C)環烷基、NR_h R_i 、OR_h 、C(O)R_h 、C(O)OR_h 、OC(O)R_h 、C(O)N(R_i )R_h 、N(R_i )C(O)R_h 、S(O)_y R_h (其中y為0、1或2)、SO₂ N(R_i )R_h 、N(R_i )SO₂ R_h 或(CH₂ )_z NR_i R_h (其中z為1、2或3)；其中R_h 及R_i 各自獨立地選自氫、(1-4C)烷基或(3-6C)環烷基； R_1a 及R_1b 係各自選自H、(1-4C)烷基、鹵基、(1-4C)鹵烷基、(1-4C)鹵烷氧基、(1-4C)烷氧基、(1-4C)烷基胺基、胺基、氰基、羥基、羧基、胺甲醯基、胺磺醯基或巰基； W選自O、S或NR¹ ，其中R¹ 選自H或(1-2C)烷基； 鍵a 、b 、c 及d 獨立地選自單鍵或雙鍵； X₁ 及X₂ 在鍵a 為雙鍵時各自獨立地選自N或CR_j ，或在鍵a 為單鍵時各自獨立地選自NR_k 或CR_i R_k ； 其中 R_j 選自氫、鹵基、(1-4C)烷基、(1-4C)烷氧基、胺基、(1-4C)烷基胺基、(1-4C)二烷基胺基、氰基、(2C)炔基、C(O)R_j1 、C(O)OR_j1 、OC(O)R_j1 、C(O)N(R_j2 )R_j1 、N(R_j2 )C(O)R_j1 、S(O)_y R_j1 (其中y為0、1或2)、SO₂ N(R_j2 )R_j1 、N(R_j2 )SO₂ R_j1 或(CH₂ )_z NR_j1 R_j2 (其中z為1、2或3)；其中該(1-4C)烷基視情況經一或多個選自以下之取代基取代：胺基、羥基、(1-2C)烷氧基或鹵基； R_k 及R_j 獨立地選自氫或(1-4C)烷基；及 R_j1 及R_j2 各自獨立地選自氫或(1-4C)烷基； X₃ 在鍵b 為雙鍵時選自N或CR_l ，或在鍵b 為單鍵時選自NR_m 或CR_l R_m ； 其中 R_l 選自氫、鹵基、(1-4C)烷基、(1-4C)烷氧基、胺基、(1-4C)烷基胺基、(1-4C)二烷基胺基、氰基、(2C)炔基、C(O)R_l1 、C(O)OR_l1 、OC(O)R_l1 、C(O)N(R_l2 )R_l1 、N(R_l2 )C(O)R_l1 、S(O)_y R_l1 (其中y為0、1或2)、SO₂ N(R_l2 )R_l1 、N(R_l2 )SO₂ R_l1 或(CH₂ )_z NR_l2 R_l1 (其中z為1、2或3)；其中該(1-4C)烷基為視情況經一或多個選自以下之取代基取代：胺基、羥基、(1-2C)烷氧基或鹵基； R_l 及R_m 獨立地選自氫或(1-4C)烷基；及 R_l1 及R_l2 各自獨立地選自氫或(1-4C)烷基； X₄ 在鍵d 為雙鍵時選自N或CR_n ，或在鍵結d 為單鍵時選自NR_o 或CR_n R_o ； 其中 R_n 選自氫、鹵基、(1-4C)烷基、(1-4C)烷氧基、胺基、(1-4C)烷基胺基、(1-4C)二烷基胺基、氰基、(2C)炔基、C(O)R_n1 、C(O)OR_n1 、OC(O)R_n1 、C(O)N(R_n2 )R_n1 、N(R_n2 )C(O)R_n1 、S(O)_y R_n1 (其中y為0、1或2)、SO₂ N(R_n2 )R_n1 、N(R_n2 )SO₂ R_n1 或(CH₂ )_z NR_n1 R_n2 (其中z為1、2或3)；其中該(1-4C)烷基視情況經一或多個選自以下之取代基取代：胺基、羥基、(1-2C)烷氧基或鹵基； R_n 及R_o 獨立地選自氫或(1-4C)烷基；及 R_n1 及R_n2 各自獨立地選自氫或(1-4C)烷基； R₂ 選自氫、(1-4C)烷基或下式之基團： -L₂ -Y₂ -Q₂ 其中： L₂ 不存在或為視情況經一或多個選自(1-2C)烷基或側氧基之取代基取代之(1-3C)伸烷基； Y₂ 不存在或為C(O)、C(O)O、C(O)N(R_p )，其中R_p 選自氫或(1-4C)烷基；及 Q₂ 為氫、(1-6C)烷基、芳基、(3-8C)環烷基、(3-8C)環烯基、雜芳基或雜環基；其中Q₂ 視情況進一步經一或多個獨立地選自以下之取代基取代：(1-4C)烷基、鹵基、(1-4C)鹵烷基、(1-4C)鹵烷氧基、胺基、氰基、羥基、羧基、胺甲醯基、胺磺醯基、NR_q R_r 、OR_q ，其中R_q 及R_r 各自獨立地選自氫、(1-4C)烷基或(3-6C)環烷基； R₃ 選自下式之基團： -Y₃ -Q₃ 其中： Y₃ 為C(O)、C(O)N(R_s )、N(R_s )(O)C、C(O)OR_s 、OC(O)CR_s 、三唑、噁二唑或四唑，其中R_s 選自氫或(1-2C)烷基；及 Q₃ 為氫、(1-6C)烷基、(1-6C)烷氧基、芳基、芳基(1-2C)烷基、(3-8C)環烷基、(3-8C)環烯基、雜芳基或雜環基；其中Q₃ 視情況進一步經一或多個獨立地選自以下之取代基取代：(1-4C)烷基、鹵基、(1-4C)鹵烷基、(1-4C)鹵烷氧基、胺基、氰基、羥基、羧基、胺甲醯基、胺磺醯基、NR_t R_u 、OR_t ，其中R_t 及R_u 各自獨立地選自氫、(1-4C)烷基或(3-6C)環烷基；或Q₃ 視情況經下式之基團取代： -L₄ -L_Q4 -Z₄ 其中： L₄ 不存在或為(1-3C)伸烷基，其視情況經一或多個選自(1-2C)烷基或側氧基之取代基取代； L_Q4 不存在或選自或為O、S、SO、SO₂ 、N(R_v )、C(O)、C(O)O、OC(O)、C(O)N(R_v )、N(R_v )C(O)、N(R_w )C(O)N(R_v )、N(R_v )C(O)O、OC(O)N(R_v )、S(O)₂ N(R_v )或N(R_v )SO₂ ，其中R_v 及R_w 各自獨立地選自氫或(1-2C)烷基；及 Z₄ 為氫、(1-6C)烷基、芳基、芳基(1-2C)烷基、(3-8C)環烷基、(3-8C)環烯基、雜芳基或雜環基；其中Z₄ 視情況經一或多個選自以下之取代基取代：(1-4C)烷基、鹵基、(1-4C)鹵烷基、(1-4C)鹵烷氧基、(1-4C)烷氧基、(1-4C)烷基胺基、胺基、氰基、羥基、羧基、胺甲醯基、胺磺醯基、巰基、脲基、芳基、雜芳基、雜環基、(3-6C)環烷基、NR_x R_y 、OR_x 、C(O)R_x 、C(O)OR_x 、OC(O)R_x 、C(O)N(R_y )R_x 、N(R_y )C(O)R_x 、S(O)_y R_x (其中y為0、1或2)、SO₂ N(R_y )R_x 、N(R_y )SO₂ R_x 或(CH₂ )_z NR_x R_y (其中z為1、2或3)；其中R_x 及R_y 各自獨立地選自氫、(1-4C)烷基或(3-6C)環烷基； 其限制條件為X₁ 、X₂ 、X₃ 或X₄ 中僅一或兩者可為N。Other exemplary RET inhibitors include compounds of formula (IX), as described in PCT Application Publication No. WO2018189553(A1 ), which is incorporated herein by reference:

Where: HET is selected from one of the following:

in

Indicates the connection point; R ₁ is selected from hydrogen, (1-4C) haloalkyl, (1-4C) haloalkoxy or a group of the following formula: -LYQ wherein: L does not exist or is (1-5C) Alkyl, which is optionally substituted by one or more substituents selected from (1-2C)alkyl or pendant oxy; Y is absent or is O, S, SO, SO ₂ , N(R _a ), C (O), C(O)O, OC(O), C(O)N(R _a ), N(R _a )C(O), N(R _a )C(O)N(R _b ), N(R _a )C(O)O, OC(O)N(R _a ), S(O) ₂ N(R _a ) or N(R _a )SO ₂ , wherein R _a and R _b are each independently selected from From hydrogen or (1-4C) alkyl; and Q is hydrogen, (1-6C) alkyl, (2-6C) alkenyl, (2-6C) alkynyl, aryl, (3-10C) cycloalkane radical, (3-10C)cycloalkenyl, heteroaryl or heterocyclyl; where Q is optionally further substituted by one or more substituents independently selected from the following: (1-4C)alkyl, halo, (1-4C) haloalkyl, (1-4C) haloalkoxy, amino, (1-4C) aminoalkyl, cyano, hydroxyl, carboxyl, carbamoyl, sulfamoyl, mercapto , ureido, NR _c R _d , OR _c , C(O)R _c , C(O)OR _c , OC(O)R _c , C(O)N(R _d )R _c , N(R _d ) C(O)R _c , S(O) _y R _c (where y is 0, 1 or 2), SO ₂ N(R _d )R _c , N(R _d )SO ₂ R _c , Si(R _d ) (R _c ) _Re or (CH ₂ ) _z NR _d R _c (wherein z is 1, 2 or 3); wherein _Re , R _d and _Re are each independently selected from hydrogen, (1-6C) alkyl or (3-6C)cycloalkyl; or R _c can be connected with R _d so that it forms a 4-7 membered heterocyclic ring together with the nitrogen atom to which it is connected, and it optionally passes one or more substituents selected from the following Substitution: (1-4C) alkyl, halo, (1-4C) haloalkyl, (1-4C) haloalkoxy, (1-4C) alkoxy, (1-4C) alkylamino , amine, cyano or hydroxyl; or Q is optionally substituted by a group of the following formula: -L ₁ -L _Q1 -Z ₁ wherein: L ₁ does not exist or is (1-3C)alkylene, which is optional Substituted by one or more substituents selected from (1-2C) alkyl or side oxygen; L _Q1 does not exist or is selected from or is O, S, SO, SO ₂ , N(R _f ), C(O ), C(O)O, OC(O), C(O)N(R _f ), N(R _f )C(O), N(R _g )C(O)N(R _f ), N( R _f ) C(O)O, OC(O)N(R _f ), S(O) ₂ N(R _f ) or N(R _f )SO ₂ , wherein R _f and R _g are each independently selected from hydrogen Or (1-2C) alkyl; and Z ₁ is hydrogen, (1-6C) alkyl, aryl, aryl (1-2C) alkyl, (3-8C) cycloalkyl, (3-8C) _Cycloalkenyl , heteroaryl or heterocyclyl; wherein Z is optionally substituted by one or more substituents selected from: (1-4C) alkyl, halo, (1-4C) haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amine, cyano, hydroxyl, carboxyl, carbamoyl, sulfamoyl, mercapto , ureido, aryl, heteroaryl, heterocyclyl, (3-6C)cycloalkyl, NR _h R _i , OR _h , C(O)R _h , C(O)OR _h , OC(O) R _h , C(O)N(R _i )R _h , N(R _i )C(O)R _h , S(O) _y R _h (where y is 0, 1 or 2), SO ₂ N(R _i ) R _h , N(R _i )SO ₂ R _h or (CH ₂ ) _z NR _i R _h (wherein z is 1, 2 or 3); wherein R _h and R _i are each independently selected from hydrogen, (1 -4C) alkyl or (3-6C) cycloalkyl; R _1a and R _1b are each selected from H, (1-4C) alkyl, halo, (1-4C) haloalkyl, (1-4C ) haloalkoxy, (1-4C) alkoxy, (1-4C) alkylamino, amino, cyano, hydroxyl, carboxyl, carbamoyl, sulfamoyl or mercapto; W is selected from O, S or NR ¹ , wherein R ¹ is selected from H or (1-2C) alkyl; bond a , b , c and d are independently selected from single bond or double bond; X ₁ and X ₂ are double bonds at bond a Each of the bonds is independently selected from N or CR _j , or each independently selected from NR _k or CR _i R _k when the bond a is a single bond; wherein R _j is selected from hydrogen, halo, (1-4C) alkyl , (1-4C) alkoxy, amino, (1-4C) alkylamino, (1-4C) dialkylamino, cyano, (2C) alkynyl, C(O)R _j1 , C(O)OR _j1 , OC(O)R _j1 , C(O)N(R _j2 )R _j1 , N(R _j2 )C(O)R _j1 , S(O) _y R _j1 (where y is 0 , 1 or 2), SO ₂ N(R _j2 )R _j1 , N(R _j2 )SO ₂ R _j1 or (CH ₂ ) _z NR _j1 R _j2 (where z is 1, 2 or 3); where the (1 -4C) alkyl is optionally substituted with one or more substituents selected from the group consisting of amino, hydroxyl, (1-2C)alkoxy or halo; R _k and R _j are independently selected from hydrogen or (1 -4C) alkyl; and _Rj1 and _Rj2 are each independently selected from hydrogen or (1-4C) alkyl; _X3 is selected from N or _CR1 when the bond b is a double bond, or is a single bond at the bond b When selected from NR _m or CR _l R _m ; wherein R _l is selected from hydrogen, halo, (1-4C) alkyl, (1-4C) alkoxy, amino, (1-4C) alkylamine , (1-4C) dialkylamino, cyano, (2C) alkynyl, C(O)R _l1 , C(O)OR _l1 , OC(O)R _l1 , C(O)N(R _l2 )R _l1 , N(R _l2 )C(O)R _l1 , S(O) _y R _l1 (where y is 0, 1 or 2), SO ₂ N(R _l2 )R _l1 , N(R _l2 )SO ₂ R ₁₁ or (CH ₂ ) _z NR ₁₂ R ₁₁ (wherein z is 1, 2 or 3); wherein the (1-4C) alkyl is optionally substituted by one or more substituents selected from the group consisting of: amine radical, hydroxyl, (1-2C) alkoxy or halo; R ₁ and R _m are independently selected from hydrogen or (1-4C) alkyl; and R ₁₁ and R ₁₂ are each independently selected from hydrogen or (1 -4C) alkyl; X ₄ is selected from N or CR _n when the bond d is a double bond, or selected from NR _o or CR _n R _o when the bond d is a single bond; wherein R _n is selected from hydrogen, halo , (1-4C) alkyl group, (1-4C) alkoxy group, amino group, (1-4C) alkyl amino group, (1-4C) dialkyl amino group, cyano group, (2C) alkynyl group , C(O)R _n1 , C(O)OR _n1 , OC(O)R _n1 , C(O)N(R _n2 )R _n1 , N(R _n2 )C(O)R _n1 , S(O) _y R _n1 (where y is 0, 1 or 2), SO ₂ N(R _n2 )R _n1 , N(R _n2 )SO ₂ R _n1 or (CH ₂ ) _z NR _n1 R _n2 (where z is 1, 2 or 3); wherein the (1-4C) alkyl is optionally substituted by one or more substituents selected from the following: amino, hydroxyl, (1-2C) alkoxy or halo; R _n and R _o independently selected from hydrogen or (1-4C) alkyl; and R _n1 and R _n2 are each independently selected from hydrogen or (1-4C) alkyl; _R2 is selected from hydrogen, (1-4C) alkyl or the following A group of the formula: -L ₂ -Y ₂ -Q ₂ wherein: L ₂ does not exist or is (1- 3C) alkylene; Y ₂ is absent or is C(O), C(O)O, C(O)N( _Rp ), wherein _Rp is selected from hydrogen or (1-4C)alkyl; and Q ₂ is hydrogen, (1-6C) alkyl, aryl, (3-8C) cycloalkyl, (3-8C) cycloalkenyl, heteroaryl or heterocyclyl; wherein _Q is further modified by one or A plurality of substituents independently selected from the following substituents: (1-4C) alkyl, halo, (1-4C) haloalkyl, (1-4C) haloalkoxy, amine, cyano, hydroxyl, Carboxyl, carbamoyl, sulfamoyl, NR _q R _r , OR _q , wherein R _q and R _r are each independently selected from hydrogen, (1-4C) alkyl or (3-6C) cycloalkyl; R ₃ is selected from groups of the following formula: -Y ₃ -Q ₃ wherein: Y ₃ is C(O), C(O)N(R _s ), N(R _s )(O)C, C(O) OR _s , OC(O)CR _s , triazole, oxadiazole or tetrazole, wherein R _s is selected from hydrogen or (1-2C)alkyl; and _Q3 is hydrogen, (1-6C)alkyl, ( 1-6C) alkoxy, aryl, aryl (1-2C) alkyl, (3-8C) cycloalkyl, (3-8C) cycloalkenyl, heteroaryl or heterocyclyl; wherein Q ₃ Optionally further substituted by one or more substituents independently selected from: (1-4C) alkyl, halo, (1-4C) haloalkyl, (1-4C) haloalkoxy, amino , cyano, hydroxyl, carboxyl, carbamoyl, sulfamoyl, NR _t R _u , OR _t , wherein R _t and R _u are each independently selected from hydrogen, (1-4C) alkyl or (3- 6C) cycloalkyl; or Q ₃ is optionally substituted by a group of the formula: -L ₄ -L _Q4 -Z ₄ wherein: L ₄ is absent or is (1-3C)alkylene, which is optionally substituted by a Or a plurality of substituents selected from (1-2C) alkyl or side oxygen; L _Q4 does not exist or is selected from or is O, S, SO, SO ₂ , N(R _v ), C(O), C(O)O, OC(O), C(O)N(R _v ), N(R _v )C(O), N(R _w )C(O)N(R _v ), N(R _v )C(O)O, OC(O)N(R _v ), S(O) ₂ N(R _v ) or N(R _v )SO ₂ , wherein R _v and R _w are each independently selected from hydrogen or ( 1-2C) alkyl; and _Z4 is hydrogen, (1-6C) alkyl, aryl, aryl (1-2C) alkyl, (3-8C) cycloalkyl, (3-8C) cycloalkene radical, _heteroaryl or heterocyclyl; wherein Z is optionally substituted by one or more substituents selected from the group consisting of: (1-4C) alkyl, halo, (1-4C) haloalkyl, (1 -4C) haloalkoxy, (1-4C) alkoxy, (1-4C) alkylamino, amine, cyano, hydroxyl, carboxyl, carbamoyl, sulfamoyl, mercapto, urea radical, aryl, heteroaryl, heterocyclyl, (3-6C)cycloalkyl, NR _x R _y , OR x , C(O)R _x , _C (O)OR _x , OC(O)R _x , C(O)N(R _y )R _x , N(R _y )C(O)R _x , S(O) _y R _x (where y is 0, 1 or 2), SO ₂ N(R _y ) R _x , N(R _y )SO ₂ R _x or (CH ₂ ) _z NR _x R _y (where z is 1, 2 or 3); wherein R _x and R _y are each independently selected from hydrogen, (1-4C ) alkyl or (3-6C) cycloalkyl; the limitation is that only one or both of X ₁ , X ₂ , X ₃ or X ₄ can be N.

或其醫藥學上可接受之鹽，其中：環A為芳基或雜芳基環； X¹ 及X² 中之每一者獨立地選自N及C(R⁶ )；Z為

、-CD(R⁵ )-或-CH(R⁵ )-，其中「1」表示與N(R⁸ )之連接點；且「2」表示與環A之連接點；各R¹ 及各R⁷ 獨立地選自C₁ -C₆ 烷基、C₂ -C₆ 烯基、C₂ -C₆ 炔基、C₁ -C₆ 烷氧基、鹵基、C₁ -C₆ 雜烷基、環烷基、芳基、雜芳基、芳基氧基、芳烷基、雜環基、雜環基烷基、硝基、氰基、-C(O)R^c 、-OC(O)R^c 、-C(O)OR^d 、-(C₁ -C₆ 伸烷基)-C(O)R^c 、-SR^d 、-S(O)₂ R^c 、-S(O)₂ -N(R^d )(R^d )、-(C₁ -C₆ 伸烷基)-S(O)₂ R^c 、-(C₁ -C₆ 伸烷基)-S(O)₂ -N(R^d )(R^d )、-N(R^d )(R^d )、-C(O)-N(R^d )(R^d )、-N(R^d )-C(O)R^c 、-N(R^d )-C(O)OR^c 、-(C1-C6伸烷基)-N(R^d )-C(O)R^c 、-N(R^d )S(O)₂ R^c 及-P(O)(R^c )(R^c )；其中烷基、烯基、炔基、烷氧基、雜烷基、環烷基、芳基、雜芳基、芳基氧基、芳烷基、雜環基及雜環基烷基中之每一者獨立地經R^a 取代0-5次；或兩個R¹ 或兩個R⁷ 與其所連接之碳原子共同形成環烷基或雜環基環，其獨立地經R^b 取代0-5次； R² 、R³ (若存在)及R⁴ 中之每一者獨立地選自氫、C₁ -C₆ 烷基、C₁ -C₆ 烷氧基、鹵基、羥基、氰基、C₁ -C₆ 雜烷基及-N(R^d )(R^d )；其中烷基、烷氧基及雜烷基中之每一者視情況且獨立地經R^a 取代0-5次； R⁵ 及R⁸ 中之每一者獨立地選自氫、氘、C₁ -C₆ 烷基及C₁ -C₆ 雜烷基；其中各烷基及雜烷基視情況且獨立地經R^a 取代0-5次；各R⁶ 獨立地選自氫、C₁ -C₆ 烷基、C₁ -C₆ 烷氧基、鹵基、氰基、C₁ -C₆ 雜烷基及-N(R^d )(R^d )；其中各烷基、烷氧基及雜烷基視情況且獨立地經R^a 取代0-5次； 各R^a 及各R^b 獨立地選自C₁ -C₆ 烷基、鹵基、羥基、C₁ -C₆ 雜烷基、C₁ -C₆ 烷氧基、環烷基、雜環基或氰基，其中烷基、雜烷基、烷氧基、環烷基及雜環基中之每一者獨立地經R'取代0-5次； 各R'獨立地選自C₁ -C₆ 烷基、C₁ -C₆ 雜烷基、鹵基、羥基、環烷基或氰基；或兩個R'與其所連接之原子共同形成環烷基或雜環基環；各R^c 獨立地選自氫、羥基、鹵基、硫醇、C₁ -C₆ 烷基、C₁ -C₆ 硫烷基、C₁ -C₆ 烷氧基、C₁ -C₆ 雜烷基、環烷基、環烷基烷基、雜芳基烷基、雜環基及雜環基烷基，其中烷基、硫烷基、烷氧基、雜烷基、環烷基、環烷基烷基、雜芳基烷基、雜環基及雜環基烷基中之每一者獨立地經R^a 取代0-5次，或兩個R^c 與其所連接之原子共同形成環烷基或雜環基環，其獨立地經R^b 取代0-5次； 各R^d 獨立地選自氫、C₁ -C₆ 烷基、C₁ -C₆ 雜烷基、環烷基、環烷基烷基、雜芳基烷基、雜環基及雜環基烷基，其中烷基、雜烷基、環烷基、環烷基烷基、雜芳基烷基、雜環基及雜環基烷基中之每一者獨立地經R^a 取代0-5次，或兩個R^d 與其所連接之原子共同形成環烷基或雜環基環，其獨立地經R^b 取代0-5次；m為0、1或2；及n為0、1、2或3。Other exemplary RET inhibitors include compounds having formula (X), as described in PCT Application Publication No. WO2018017983(A1 ), which is incorporated herein by reference:

or a pharmaceutically acceptable salt thereof, wherein: Ring A is an aryl or heteroaryl ring; each of X ¹ and X ² is independently selected from N and C(R ⁶ ); Z is

, -CD(R ⁵ )- or -CH(R ⁵ )-, wherein "1" represents the connection point with N(R ⁸ ); and "2" represents the connection point with ring A; each R ¹ and each R ⁷ are independently selected from C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, halo, C ₁ -C ₆ heteroalkyl, Cycloalkyl, aryl, heteroaryl, aryloxy, aralkyl, heterocyclyl, heterocyclylalkyl, nitro, cyano, -C(O)R ^c , -OC(O)R ^c , -C(O)OR ^d , -(C ₁ -C ₆ alkylene)-C(O)R ^c , -SR ^d , -S(O) ₂ R ^c , -S(O) ₂ -N (R ^d )(R ^d ), -(C ₁ -C ₆ alkylene) -S(O) ₂ R ^c , -(C ₁ -C ₆ alkylene) -S(O) ₂ -N(R ^d )(R ^d ), -N(R ^d )(R ^d ), -C(O)-N(R ^d )(R ^d ), -N(R ^d )-C(O)R ^c , -N (R ^d )-C(O)OR ^c , -(C1-C6 alkylene)-N(R ^d )-C(O)R ^c , -N(R ^d )S(O) ₂ R ^c and - P(O)(R ^c )(R ^c ); where alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, aryl, heteroaryl, aryloxy, aralkyl Each of , heterocyclyl and heterocyclylalkyl is independently substituted by ^R 0-5 times; or two R ¹ or two R ⁷ and the carbon atom to which they are attached together form a cycloalkyl or heterocyclic ring A base ring, which is independently substituted 0-5 times by R ^b ; each of R ² , R ³ (if present) and R ⁴ is independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halo, hydroxy, cyano, C ₁ -C ₆ heteroalkyl and -N(R ^d )(R ^d ); wherein each of alkyl, alkoxy and heteroalkyl is and independently substituted by R ^a for ^0-5 times; each of R and R is independently selected ^from hydrogen, deuterium, C ₁ -C ₆ alkyl and C ₁ -C ₆ heteroalkyl; wherein each Alkyl and heteroalkyl are optionally and independently substituted by R ^a for 0-5 times; ^each R is independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halo, cyano Group, C ₁ -C ₆ heteroalkyl and -N(R ^d )(R ^d ); wherein each alkyl, alkoxy and heteroalkyl are optionally and independently substituted by R ^a for 0-5 times; each R ^a and each R ^b are independently selected from C ₁ -C ₆ alkyl, halo, hydroxyl, C ₁ -C ₆ heteroalkyl, C ₁ -C ₆ alkoxy, cycloalkyl, heterocyclyl or cyano , wherein each of alkyl, heteroalkyl, alkoxy, cycloalkyl and heterocyclyl is independently substituted 0-5 times by R'; each R' is independently selected from C ₁ -C ₆ alkyl , C ₁ -C ₆ heteroalkyl, halo, hydroxyl, cycloalkyl or cyano; or two R' and the atoms to which they are attached together form a cycloalkyl or heterocyclyl ring; each R ^c is independently selected from Hydrogen, hydroxyl, halo, thiol, C ₁ -C ₆ alkyl, C ₁ -C ₆ sulfanyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ heteroalkyl, cycloalkyl, cyclo Alkylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl, where alkyl, sulfanyl, alkoxy, heteroalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl Each of alkyl, heterocyclyl and heterocyclylalkyl is independently substituted 0-5 times by ^R , or two ^R and the atoms to which they are attached together form a cycloalkyl or heterocyclyl ring, which independently substituted by R ^b for 0-5 times; each R ^d is independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl Alkyl, heterocyclyl and heterocyclylalkyl, wherein each of alkyl, heteroalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl or independently substituted by R ^a for 0-5 times, or two R ^d and the atoms to which they are attached together form a cycloalkyl or heterocyclyl ring, which is independently substituted by R ^b for 0-5 times; m is 0, 1 or 2; and n is 0, 1, 2 or 3.

其中A表示選自下式(Ia)至(Id)中之一者：

其中R¹ 表示氫原子或C1-C3烷基，且R² 表示氫原子或C1-C3烷基，或其醫藥學上可接受之鹽。Exemplary RET inhibitors include compounds having formula (XI), as described in PCT Application Publication No. WO2018060714(A1 ), which is incorporated herein by reference:

wherein A represents one of the following formulas (Ia) to (Id):

Wherein R ¹ represents a hydrogen atom or a C1-C3 alkyl group, and R ² represents a hydrogen atom or a C1-C3 alkyl group, or a pharmaceutically acceptable salt thereof.

Other therapeutic agents include RET inhibitors, such as described in, e.g., U.S. Patent Nos. 10,030,005; 10,035,789; 9,988,371; 9,938,274; 772 No. 9,493,455; No. 9,758,508; No. 9,604,980; No. 9,321,772; ; No. 8,895,744; No. 8,629,135; No. 8,815,906; No. 8,354,526; No. 8,741,849; No. 8,461,161; No. 8,524,709; ,863,288; No. 7,465,726; No. 8,552,002 8,067,434; 8,198,298; 8,106,069; 6,861,509; 9,150,517; 9,149,464; /0009818; No. No. 2018/0009817; No. 2017/0283404; No. 2017/0267661; No. 2017/0298074; No. 2017/0114032; 015/ No. 0099721; No. 2014/0371219; No. 2014/0137274; No. 2013/0079343; No. 2012/0283261; 302567 ; No. 2011/0189167; No. 2016/0046636; No. 2013/0012703; No. No. 2011/0046370; No. 2010/0280012; No. 2012/0070410; No. 2010/0081675; No. 2010/0075916; 009/ No. 0099167; No. 2010/0209488; No. 2009/0012045; No. 2013/0303518; No. 2008/0234267; 173954 ; No. 2011/0195072; No. 2010/0004239; No. 2007/0149523; No. No. 2015/0065468; No. 2009/0069360; No. 2008/0275054; No. 2007/0117800; No. 2008/0234284; 008/ No. 0319005; No. 2009/0215761; No. 2008/0287427; No. 2006/0183900; No. 2005/0222171; 143399 ; 2009/0130229; 2007/0265274; 2004/0185547; and 2016/0176865; and International Publication Nos. WO 2018/136796; WO 2018/189553; ; WO 2018/035072; WO 2018/049127; WO 2018/060714; WO 2018/102455; WO 2018/149382; WO 2017/145050; WO 2017/097697; WO 2017/049462; WO 2017/043550; WO 2017/027883; WO 2017/013160; WO 2017/009644; WO 2016/168992; WO 2016/137060; WO 2016/127074; WO 2016/075224; WO 2016/038552; WO 2015/079251; 2013/042137; WO 2013/036232; WO 2013/016720; WO 2012/053606; WO 2012/047017; WO 2007/109045; /023978; WO 2009/017838; WO 2017/178845; WO 2017/178844; WO 2017/146116; WO 2017/026718; WO 2016/096709; 057397; WO 2007/057399; WO 2007/054357; WO 2006/130613; WO 2006/089298; WO 2005/070431; WO 2003/020698; WO 2001/016169; WO 1997/044356; WO 2007/087245; WO 2005/044835; WO 2014/075035; and WO 2016/038519; and J. Med. Chem. 2012, 55 (10), 4872-4876, all of which are incorporated herein by reference in their entirety.

或其醫藥學上可接受之鹽或溶劑合物，其中： X¹ 為CH、CCH₃ 、CF、CCl或N； X² 為CH、CF或N； X³ 為CH、CF或N； X⁴ 為CH、CF或N； 其中X¹ 、X² 、X³ 及X⁴ 中之零、一或兩者為N； A為H、Cl、CN、Br、CH₃ 、CH₂ CH₃ 或環丙基； B為hetAr¹ ； hetAr¹ 為具有1-3個獨立地選自N、秒及O之環雜原子之5員雜芳基環，其中該雜芳基環視情況經一或多個獨立地選自由以下組成之群之取代基取代：鹵素、C1-C6烷基、羥基C1-C6烷基、氟C1-C6烷基、二氟C1-C6烷基、三氟C1-C6烷基、氰基C1-C6烷基、(C1-C6烷氧基)C1-C6烷基、(C1-C4烷氧基)CH₂ C(=O)-、(C1-C4烷氧基)C(=O)C1-C3烷基、C3-C6環烷基、(R^a R^b N)C1-C6烷基、(R^a R^b N)C(=O)C1-C6烷基、(C1-C6烷基SO₂ )C1-C6烷基、hetCyc^a 及4-甲氧基苯甲基； R^a 及R^b 獨立地為H或C₁ -C₆ 烷基； hetCyc^a 為具有選自N及O之環雜原子之4-6員雜環，其中該雜環視情況經以下取代：鹵素、C1-C6烷基、氟C1-C6烷基、二氟C1-C6烷基、三氟C1-C6烷基、(C1-C6烷氧基)C1-C6烷基、二(C1-C3烷基)NCH₂ C(=O)、(C1-C6烷氧基)C(=O)或(C1-C6烷氧基)CH₂ C(=O)； D為hetCyc¹ 、hetCyc² 、hetCyc³ 或hetCyc⁹ ； hetCyc¹ 為具有1-2個選自N及O之環原子之4-6員雜環，其中該雜環視情況經一或多個獨立地選自由以下組成之群之取代基取代：C1-C3烷基、氟C1-C3烷基、二氟C1-C3烷基、三氟C1-C3烷基及OH，或該雜環經C3-C6亞環烷基環取代，或該雜環經側氧基取代； hetCyc² 為具有1-3個獨立地選自N及O之環雜原子之7-8員橋連雜環，其中該雜環視情況經C1-C3烷基取代； hetCyc³ 為具有1-2個獨立地選自N及O之環雜原子之7-11員螺雜環，其中該環視情況經C1-C3烷基取代； hetCyc⁹ 為稠合之9-10員雜環，其具有1-3個環氮原子且視情況經側氧基取代； E為 (a) 氫， (b) OH， (c) R^a R^b N-，其中R^a 為H或C1-C6烷基且R^b 為H、C1-C6烷基或苯基； (d) C1-C6烷基，其視情況經一至三個氟取代， (e) 羥基C1-C6烷基-，其視情況經一至三個氟取代， (f) C1-C6烷氧基，其視情況經一至三個氟取代， (g) 羥基(C1-C6烷氧基)，其視情況經一至三個氟取代， (h) (C1-C6烷氧基)羥基C1-C6烷基-，其視情況經一至三個氟取代， (i) (C1-C6烷基)C(=O)-，其視情況經一至三個氟取代， (j) (羥基C1-C6烷基)C(=O)-，其視情況經一至三個氟取代， (k) (C1-C6烷氧基)C(=O)-， (l) (C1-C6烷氧基)(C1-C6烷基)C(=O)-， (m) HC(=O)-， (n) Cyc¹ ， (o) Cyc¹ C(=O)-， (p) Cyc¹ (C1-C6烷基)C(=O)-，其中該烷基部分視情況經一或多個獨立地選自由以下組成之群之基團取代：OH、氟、C1-C3烷氧基及R^c R^d N-，其中R^c 及R^d 獨立地為H或C1-C6烷基， (q) hetCyc⁴ ， (r) hetCyc⁴ C(=O)-， (s) hetCyc⁴ (C1-C3烷基)C(=O)-， (t) (hetCyc⁴ )C(=O)C1-C2烷基-， (u) hetCyc⁴ C(=O)NH-， (v) Ar² ， (w) Ar² C(=O)-， (x) Ar² C1-C6烷基-， (y) (Ar² )羥基C2-C6烷基-， (z) Ar² (C1-C3烷基)C(=O)-，其中該烷基部分視情況經一或兩個獨立地選自由以下組成之群之基團取代：OH、C1-C6烷基(視情況經1-3個氟取代)、羥基C1-C6烷基、C1-C6烷氧基及R^e R^f N-，其中R^e 及R^f 獨立地為H或C1-C6烷基，或R^e 及R^f 與其所連接之氮共同形成5-6員氮雜環，其視情況具有選自N及O之其他環雜原子， (aa) hetAr² C(=O)-， (bb) (hetAr² )羥基C2-C6烷基-， (cc) hetAr² (C1-C3烷基)C(=O)-，其中該烷基部分視情況經一或兩個獨立地選自由以下組成之群之基團取代：OH、C1-C6烷基、羥基C1-C6烷基、C1-C6烷氧基及R^e R^f N-，其中R^e 及R^f 獨立地為H或C1-C6烷基或R^e 及R^f 與其所連接之氮共同形成5-6員氮雜環，其視情況具有選自N及O之其他環雜原子， (dd) R¹ R² NC(=O)-， (ee) R¹ R² N(C1-C3烷基)C(=O)-，其中該烷基部分視情況經苯基取代， (ff) R¹ R² NC(=O)C1-C2烷基-， (gg) R¹ R² NC(=O)NH-， (hh) CH₃ SO₂ (C1-C6烷基)C(=O)-， (ii) (C1-C6烷基)SO₂ -， (jj) (C3-C6環烷基)CH₂ SO₂ -， (kk) hetCyc⁵ -SO₂ -， (ll) R⁴ R⁵ NSO₂ -， (mm) R⁶ C(=O)NH-， (nn) hetCyc⁶ ， (oo) hetAr² C1-C6烷基-， (pp) (hetCyc⁴ )C1-C6烷基-， (qq) (C1-C6烷氧基)C1-C6烷基-，其視情況經1-3個氟取代， (rr) (C3-C6環烷氧基)C1-C6烷基-， (ss) (C3-C6環烷基)C1-C6烷基-，其中該環烷基視情況經1-2個氟取代， (tt) (R^g R^h N)C1-C6烷基-，其中R^g 及R^h 獨立地為H或C1-C6烷基， (uu) Ar² -O-， (vv) (C1-C6烷基SO₂ )C1-C6烷基-， (ww) (C1-C6烷氧基)C(=O)NHC1-C6烷基-， (xx) (C3-C6換烷氧基)C(=O)-， (yy) (C3-C6環烷基)SO₂ -，其中該環烷基視情況經C1-C6烷基取代， (zz) Ar⁴ CH₂ OC(=O)-， (aaa) (N-(C1-C3烷基)吡啶酮基)C1-C3烷基-，及 (bbb) (Ar⁴ SO₂ )C1-C6烷基-； Cyc¹ 為C3-C6環烷基，其中(a)該環烷基視情況經一或多個獨立地選自由以下組成之群之取代基取代：OH、鹵素、C1-C6烷氧基、CN、羥基C1-C6烷基、(C1-C6烷氧基)C1-C6烷基及C1-C6烷基，其視情況經1-3個氟取代；或(b)該環烷基經苯基取代，其中該苯基視情況經一或多個獨立地選自由以下組成之群之取代基取代：鹵素、C1-C3烷基、C1-C3烷氧基及CF；或(c)該環烷基經具有1-3個獨立地選自N及O之環雜原子之5-6員雜芳基環取代，其中該雜芳基環視情況經一或多個獨立地選自由以下組成之群之取代基取代：鹵素、C1-C3烷基、C1-C3烷氧基及CF₃ ； Ar² 為苯基，視情況經一或多個獨立地選自由以下組成之群治取代基取代：鹵素、C1-C6烷基、C1-C6烷氧基(視情況經1-3個氟取代)、氟C1-C6烷基、二氟C1-C6烷基、三氟C1-C6烷基、CN、具有1-2個獨立地選自N及O之環雜原子之5-6員雜環及Rⁱ R^j N-，其中Rⁱ 及R^j 獨立地為H或C1-C6烷基； hetAr² 為5-6員雜芳基環，其具有1-3個獨立地選自N、O及S之環雜原子且視情況經一或多個獨立地選自由以下組成之群之取代基取代：鹵素、C1-C6烷基、C1-C6烷氧基(視情況經1-3個氟取代)、氟C1-C6烷基、二氟C1-C6烷基、三氟C1-C6烷基、羥基C1-C6烷基、(C3-C6)環烷基、(C1-C6烷氧基)C1-C6烷基、CN、OH及R'R''N-，其中R'及R''獨立地為H或C1-C3烷基； hetCyc⁴ 為(a)4-6員雜環，其具有1-2個獨立地選自N、O及S之環雜原子，其中該S視情況氧化成SO₂ ；(b)7-8員橋連雜環，其具有1-2個獨立地選自N及O之環雜原子；(c)6-12員稠合雙環雜環，其具有1-2個獨立地選自N及O之環雜原子且視情況獨立地經1-2個C1-C6烷基取代基取代；或(d)7-10員螺環雜環，其具有1-2個獨立地選自N及O之環雜原子，其中該等雜環中之每一者視情況經一或多個獨立地選自由以下組成之群之取代基取代：鹵素、OH、CN、C1-C6烷基(視情況經1-3個氟取代)、C1-C6烷氧基、(C1-C6烷氧基)C1-C6烷基、(C3-C6)環烷基、(C1-C6烷基)C(=O)-、具有1-2個獨立地選自N及O之環雜原子之5-6員雜環及苯基，其中該苯基視情況經一或多個選自鹵素、C1-C6烷基及C1-C6烷氧基之取代基取代； hetCyc⁵ 為具有選自O及N之環雜原子之5-6員雜環； hetCyc⁶ 為具有一或兩個獨立地選自N及O之環雜原子之5員雜環，其中該環經側氧基取代且其中該環視情況進一步經一或多個獨立地選自由OH及C1-C6烷基組成之群的取代基取代； R¹ 為H、C1-C6烷基或(C1-C6烷氧基)C1-C6烷基； R² 為H、C1-C6烷基(視情況經1-3個氟取代)、(C1-C6烷氧基)C1-C6烷基(視情況經1-3個氟取代)、Cyc³ 、羥基C1-C6烷基(視情況經1-3個氟取代)、C1-C6烷氧基(視情況經1-3個氟取代)、(C1-C6烷氧基)C(=O)、hetCyc⁷ 、Ar³ 、Ar³ C1-C3烷基-、羥基C1-C6烷氧基或(3-6C環烷基)CH₂ O-； Cyc³ 為3-6員碳環，視情況經1-2個獨立地選自由C1-C6烷氧基、OH及鹵素組成之群之基團取代； hetCyc⁷ 為具有選自O及N之環雜原子之5-6員雜環，其中該環視情況經C1-C6烷基取代； Ar³ 為苯基，其視情況經一或多個獨立地選自以下之取代基取代：鹵素、C1-C3烷基、C1-C3烷氧基、氟C1-C3烷基、二氟C1-C3烷基及三氟C1-C3烷基； R⁴ 及R⁵ 獨立地為H或C1-C6烷基； R⁶ 為C1-C6烷基、羥基C1-C6烷基、C1-C6烷氧基、(C1-C6烷氧基)C1-C6烷基、苯基或hetCyc⁸ ； hetCyc⁸ 為具有選自O及N之環雜原子之5-6員雜環，其中該雜環視情況經C1-C6烷基取代；及 Ar⁴ 為苯基，其視情況經一或多個鹵素取代。In some embodiments, the RET inhibitor (eg, a first RET inhibitor or a second RET inhibitor) is a compound of formula II :

or a pharmaceutically acceptable salt or solvate thereof, wherein: X ¹ is CH, CCH ₃ , CF, CCl or N; X ² is CH, CF or N; X ³ is CH, CF or N; X ⁴ is CH, CF or N; among them, zero, one or both of X ¹ , X ² , X ³ and X ⁴ are N; A is H, Cl, CN, Br, CH ₃ , CH ₂ CH ₃ or cyclopropane B is hetAr ¹ ; hetAr ¹ is a 5-membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, S and O, wherein the heteroaryl ring is optionally modified by one or more independently Substituents selected from the group consisting of: halogen, C1-C6 alkyl, hydroxy C1-C6 alkyl, fluoro C1-C6 alkyl, difluoro C1-C6 alkyl, trifluoro C1-C6 alkyl, cyanide C1-C6 alkyl, (C1-C6 alkoxy) C1-C6 alkyl, (C1-C4 alkoxy) CH ₂ C(=O)-, (C1-C4 alkoxy) C(=O ) C1-C3 alkyl, C3-C6 cycloalkyl, (R ^a R ^b N) C1-C6 alkyl, (R ^a R ^b N) C (= O) C1-C6 alkyl, (C1-C6 alkane group SO ₂ ) C1-C6 alkyl, hetCyc ^a and 4-methoxybenzyl; R ^a and R ^b are independently H or C ₁ -C ₆ alkyl; hetCyc ^a is selected from N and O 4-6 membered heterocycles with ring heteroatoms, wherein the heterocycles are optionally substituted by: halogen, C1-C6 alkyl, fluoroC1-C6 alkyl, difluoroC1-C6 alkyl, trifluoroC1-C6 alkyl , (C1-C6 alkoxy) C1-C6 alkyl, two (C1-C3 alkyl) NCH ₂ C (= O), (C1-C6 alkoxy) C (= O) or (C1-C6 alkane Oxygen) CH ₂ C (=O); D is hetCyc ¹ , hetCyc ² , hetCyc ³ or hetCyc ⁹ ; hetCyc ¹ is a 4-6 membered heterocyclic ring having 1-2 ring atoms selected from N and O, wherein The heterocycle is optionally substituted with one or more substituents independently selected from the group consisting of: C1-C3 alkyl, fluoroC1-C3 alkyl, difluoroC1-C3 alkyl, trifluoroC1-C3 alkyl and OH, or the heterocyclic ring is substituted by a C3-C6 cycloalkylene ring, or the heterocyclic ring is substituted by a side oxy group; hetCyc ² is a 7- ring heteroatom with 1-3 independently selected from N and O 8-membered bridged heterocyclic ring, wherein the heterocyclic ring is optionally substituted by C1-C3 alkyl; hetCyc ³ is a 7-11 membered spiro heterocyclic ring with 1-2 ring heteroatoms independently selected from N and O, wherein the The ring is optionally substituted by C1-C3 alkyl; ^hetCyc9 is a fused 9-10 membered heterocyclic ring having 1-3 ring nitrogen atoms and optionally substituted by a pendant oxygen group; E is (a) hydrogen, (b ) OH, (c) R ^a R ^b N-, wherein R ^a is H or C1-C6 alkyl and R ^b is H, C1-C6 alkyl or phenyl; (d) C1-C6 alkyl, depending on optionally substituted by one to three fluorines, (e) hydroxyC1-C6 alkyl-, optionally substituted by one to three fluorines, (f) C1-C6 alkoxy, optionally substituted by one to three fluorines, ( g) hydroxy(C1-C6 alkoxy), which is optionally substituted by one to three fluorines, (h) (C1-C6 alkoxy) hydroxyC1-C6 alkyl-, which is optionally substituted by one to three fluorines , (i) (C1-C6 alkyl)C(=O)-, which is optionally substituted by one to three fluorines, (j) (hydroxylC1-C6 alkyl)C(=O)-, which is optionally substituted by One to three fluorine substitutions, (k) (C1-C6 alkoxy) C (=O)-, (l) (C1-C6 alkoxy) (C1-C6 alkyl) C (=O)-, ( m) HC(=O)-, (n) Cyc ¹ , (o) Cyc ¹ C(=O)-, (p) Cyc ¹ (C1-C6 alkyl) C(=O)-, wherein the alkyl Part is optionally substituted with one or more groups independently selected from the group consisting of OH, fluorine ^, C1-C3 alkoxy and ^RcRdN- , wherein ^Rc and ^Rd are independently H or C1-C6 alkyl, (q) hetCyc ⁴ , (r) hetCyc ⁴ C(=O)-, (s) hetCyc ⁴ (C1-C3 alkyl)C(=O)-, (t) (hetCyc ⁴ ) C(=O)C1-C2 alkyl-, (u) hetCyc ⁴ C(=O)NH-, (v) Ar ² , (w) Ar ² C(=O)-, (x) Ar ² C1- C6 alkyl-, (y) (Ar ² ) hydroxy C2-C6 alkyl-, (z) Ar ² (C1-C3 alkyl) C (= O)-, wherein the alkyl moiety is optionally modified by one or two Substituted by a group independently selected from the group consisting of OH, C1-C6 alkyl (optionally substituted by 1-3 fluorine), hydroxyC1-C6 alkyl, C1-C6 alkoxy and R ^e R ^f N-, wherein R ^e and R ^f are independently H or C1-C6 alkyl, or R ^e and R ^f form a 5-6-membered nitrogen heterocyclic ring together with the nitrogen to which they are attached, which, as the case may be, have a group selected from N and Other ring heteroatoms of O, (aa) hetAr ² C(=O)-, (bb) (hetAr ² ) hydroxy C2-C6 alkyl-, (cc) hetAr ² (C1-C3 alkyl) C(=O )-, wherein the alkyl moiety is optionally substituted by one or two groups independently selected from the group consisting of: OH, C1-C6 alkyl, hydroxyC1-C6 alkyl, C1-C6 alkoxy and R ^e R ^f N-, wherein R ^e and R ^f are independently H or C1-C6 alkyl or R ^e and R ^f form a 5-6 membered nitrogen heterocycle together with the nitrogen to which they are attached, which optionally has Other ring heteroatoms of N and O, (dd) R ¹ R ² NC(=O)-, (ee) R ¹ R ² N(C1-C3 alkyl)C(=O)-, wherein the alkyl moiety Optionally substituted with phenyl, (ff) R ¹ R ² NC(=O)C1-C2 alkyl-, (gg) R ¹ R ² NC(=O)NH-, (hh) CH ₃ SO ₂ (C1 -C6 alkyl) C(=O)-, (ii) (C1-C6 alkyl) SO ₂ -, (jj) (C3-C6 cycloalkyl) CH ₂ SO ₂ -, (kk) hetCyc ⁵ -SO _2- , (ll) R ⁴ R ⁵ NSO _2- , (mm) R ⁶ C(=O)NH-, (nn) hetCyc ⁶ , (oo) hetAr ² C1-C6 alkyl-, (pp) (hetCyc ⁴ ) C1-C6 alkyl-, (qq) (C1-C6 alkoxy) C1-C6 alkyl-, which is optionally substituted by 1-3 fluorine, (rr) (C3-C6 cycloalkoxy) C1-C6 alkyl-, (ss) (C3-C6 cycloalkyl) C1-C6 alkyl-, wherein the cycloalkyl is optionally substituted by 1-2 fluorine, (tt) (R ^g R ^h N) C1-C6 alkyl-, wherein R ^g and R ^h are independently H or C1-C6 alkyl, (uu) Ar ² -O-, (vv) (C1-C6 alkylSO ₂ )C1-C6 alkyl -, (ww) (C1-C6 alkoxy) C (= O) NHC1-C6 alkyl -, (xx) (C3-C6 for alkoxy) C ( = O) -, (yy) (C3- C6 cycloalkyl)SO ₂ -, wherein the cycloalkyl is optionally substituted by C1-C6 alkyl, (zz) Ar ⁴ CH ₂ OC(=O)-, (aaa) (N-(C1-C3 alkyl ) pyridonyl) C1-C3 alkyl-, and (bbb) (Ar ⁴ SO ₂ ) C1-C6 alkyl-; Cyc ¹ is C3-C6 cycloalkyl, wherein (a) the cycloalkyl is optionally passed One or more substituents independently selected from the group consisting of: OH, halogen, C1-C6 alkoxy, CN, hydroxy C1-C6 alkyl, (C1-C6 alkoxy) C1-C6 alkyl And C1-C6 alkyl, which is optionally substituted by 1-3 fluorine; or (b) the cycloalkyl is substituted by phenyl, where the phenyl is optionally one or more independently selected from the group consisting of The substituent is substituted by: halogen, C1-C3 alkyl, C1-C3 alkoxy and CF; or (c) the cycloalkyl has 1-3 ring heteroatoms independently selected from N and O through 5- A 6-membered heteroaryl ring substituted, wherein the heteroaryl ring is optionally substituted with one or more substituents independently selected from the group consisting of: halogen, C1-C3 alkyl, C1-C3 alkoxy and _CF3 ; Ar ² is phenyl, optionally substituted by one or more substituents independently selected from the group consisting of: halogen, C1-C6 alkyl, C1-C6 alkoxy (optionally via 1-3 fluorine substituted), fluoro C1-C6 alkyl, difluoro C1-C6 alkyl, trifluoro C1-C6 alkyl, CN, 5-6 membered heteroatoms with 1-2 ring heteroatoms independently selected from N and O Ring and R ⁱ R ^j N-, wherein R ⁱ and R ^j are independently H or C1-C6 alkyl; hetAr ² is a 5-6 membered heteroaryl ring, which has 1-3 independently selected from N, The ring heteroatoms of O and S are optionally substituted by one or more substituents independently selected from the group consisting of: halogen, C1-C6 alkyl, C1-C6 alkoxy (optionally via 1-3 Fluorine substituted), fluoro C1-C6 alkyl, difluoro C1-C6 alkyl, trifluoro C1-C6 alkyl, hydroxyl C1-C6 alkyl, (C3-C6) cycloalkyl, (C1-C6 alkoxy ) C1-C6 alkyl, CN, OH and R'R''N-, wherein R' and R'' are independently H or C1-C3 alkyl; hetCyc ⁴ is (a) 4-6 membered heterocycle, It has 1-2 ring heteroatoms independently selected from N, O and S, wherein the S is optionally oxidized to SO ₂ ; (b) a 7-8 membered bridged heterocycle has 1-2 independently Ring heteroatoms selected from N and O; (c) 6-12 membered fused bicyclic heterocycles having 1-2 ring heteroatoms independently selected from N and O and optionally 1-2 ring heteroatoms independently C1-C6 alkyl substituent substitution; or (d) 7-10 membered spirocyclic heterocyclic rings, which have 1-2 ring heteroatoms independently selected from N and O, wherein each of these heterocyclic rings Optionally substituted with one or more substituents independently selected from the group consisting of: halogen, OH, CN, C1-C6 alkyl (optionally substituted with 1-3 fluorine), C1-C6 alkoxy, (C1-C6 alkoxy) C1-C6 alkyl, (C3-C6) cycloalkyl, (C1-C6 alkyl) C (= O) -, with 1-2 independently selected from N and O 5-6 membered heterocycles and phenyl ring heteroatoms, wherein the phenyl is optionally substituted by one or more substituents selected from halogen, C1-C6 alkyl and C1-C6 alkoxy; hetCyc ⁵ has A 5-6 membered heterocyclic ring with ring heteroatoms selected from O and N; hetCyc ⁶ is a 5-membered heterocyclic ring with one or two ring heteroatoms independently selected from N and O, wherein the ring is substituted by a pendant oxy group And wherein the ring is further substituted by one or more substituents independently selected from the group consisting of OH and C1-C6 alkyl; ^R1 is H, C1-C6 alkyl or (C1-C6 alkoxy)C1 -C6 alkyl; R ² is H, C1-C6 alkyl (substituted by 1-3 fluorine as appropriate), (C1-C6 alkoxy) C1-C6 alkyl (substituted by 1-3 fluorine as appropriate ), Cyc ³ , hydroxy C1-C6 alkyl (substituted by 1-3 fluorine as appropriate), C1-C6 alkoxy (substituted by 1-3 fluorine as appropriate), (C1-C6 alkoxy) C (=O), hetCyc ⁷ , Ar ³ , Ar ³ C1-C3 alkyl-, hydroxyl C1-C6 alkoxy or (3-6C cycloalkyl) CH ₂ O-; Cyc ³ is a 3-6 membered carbocycle , optionally substituted by 1-2 groups independently selected from the group consisting of C1-C6 alkoxy, OH and halogen; hetCyc ⁷ is a 5-6 membered heterocyclic ring having ring heteroatoms selected from O and N , wherein the ring is optionally substituted by C1-C6 alkyl; Ar ³ is phenyl, which is optionally substituted by one or more substituents independently selected from the following: halogen, C1-C3 alkyl, C1-C3 alkoxy fluoro C1-C3 alkyl, difluoro C1-C3 alkyl and trifluoro C1-C3 alkyl; R ⁴ and R ⁵ are independently H or C1-C6 alkyl; R ⁶ is C1-C6 alkyl, Hydroxy C1-C6 alkyl, C1-C6 alkoxy, (C1-C6 alkoxyl) C1-C6 alkyl, phenyl or hetCyc ⁸ ; hetCyc ⁸ is a 5- ring heteroatom with O and N 6-membered heterocycle, wherein the heterocycle is optionally substituted with C1-C6 alkyl; and Ar ⁴ is phenyl, which is optionally substituted with one or more halogens.

或其醫藥學上可接受之鹽或溶劑合物，其中： X¹ 為CH或N； X² 為CH或N； X³ 為CH或N； X⁴ 為CH或N； 其中X¹ 、X² 、X³ 及X⁴ 中之一或兩者為N； A為CN； B為hetAr¹ ； hetAr¹ 為5員雜芳基環，其具有1-3個環氮原子，其中該雜芳基環視情況經一或多個獨立地選自由以下組成之群之取代基取代：鹵素、C1-C6烷基、羥基C1-C6烷基、氟C1-C6烷基、二氟C1-C6烷基、三氟C1-C6烷基、氰基C1-C6烷基、(C1-C6烷氧基)C1-C6烷基、(C1-C4烷氧基)CH₂ C(=O)-、(C1-C4烷氧基)C(=O)C1-C3烷基、C3-C6環烷基、(R^a R^b N)C1-C6烷基、(R^a R^b N)C(=O)C1-C6烷基、(C1-C6烷基SO₂ )C1-C6烷基及4-甲氧基苯甲基； R^a 及R^b 獨立地為H或C₁ -C₆ 烷基； D為hetCyc¹ ； hetCyc¹ 為4-6員雜環，其具有1-2個環氮原子，其中該雜環視情況經一或多個獨立地選自由以下組成之群之取代基取代：C1-C3烷基、氟C1-C3烷基、二氟C1-C3烷基、三氟C1-C3烷基及OH，或該雜環經C3-C6亞環烷基環取代，或該雜環經側氧基取代； E為 (w) Ar² C(=O)-， (x) Ar² C1-C6烷基-， (z) Ar² (C1-C3烷基)C(=O)-，其中該烷基部分視情況經一或兩個獨立地選自由以下組成之群之基團取代：OH、C1-C6烷基(視情況經1-3個氟取代)、羥基C1-C6烷基、C1-C6烷氧基及R^e R^f N-，其中R^e 及R^f 獨立地為H或C1-C6烷基，或R^e 及R^f 與其所連接之氮共同形成5-6員氮雜環，其視情況具有選自N及O之其他環雜原子， (cc) hetAr² (C1-C3烷基)C(=O)-，其中該烷基部分視情況經一或兩個獨立地選自由以下組成之群之基團取代：OH、C1-C6烷基、羥基C1-C6烷基、C1-C6烷氧基及R^e R^f N-，其中R^e 及R^f 獨立地為H或C1-C6烷基或R^e 及R^f 與其所連接之氮共同形成5-6員氮雜環，其視情況具有選自N及O之其他環雜原子， (dd) R¹ R² NC(=O)-， (oo) hetAr² C1-C6烷基-， Ar² 為苯基，其視情況經一或多個獨立地選自由以下組成之群之取代基取代：鹵素、C1-C6烷基、C1-C6烷氧基(視情況經1-3個氟取代)、氟C1-C6烷基、二氟C1-C6烷基、三氟C1-C6烷基、CN、具有1-2個獨立地選自N及O之環雜原子之5-6員雜環及Rⁱ R^j N-，其中Rⁱ 及R^j 獨立地為H或C1-C6烷基； hetAr² 為5-6員雜芳基環，其具有1-3個獨立地選自N、O及S之環雜原子且視情況經一或多個獨立地選自由以下組成之群之取代基取代：鹵素、C1-C6烷基、C1-C6烷氧基(視情況經1-3個氟取代)、氟C1-C6烷基、二氟C1-C6烷基、三氟C1-C6烷基、羥基C1-C6烷基、(C3-C6)環烷基、(C1-C6烷氧基)C1-C6烷基、CN、OH及R'R''N-，其中R'及R''獨立地為H或C1-C3烷基； R¹ 為H、C1-C6烷基或(C1-C6烷氧基)C1-C6烷基；及 R² 為H、C1-C6烷基(視情況經1-3個氟取代)、(C1-C6烷氧基)C1-C6烷基(視情況經1-3個氟取代)、羥基C1-C6烷基(視情況經1-3個氟取代)、C1-C6烷氧基(視情況經1-3個氟取代)、(C1-C6烷氧基)C(=O)、羥基C1-C6烷氧基或(3-6C環烷基)CH₂ O。In some embodiments, the RET inhibitor (eg, a first RET inhibitor or a second RET inhibitor) is a compound of formula III :

or a pharmaceutically acceptable salt or solvate thereof, wherein: X ¹ is CH or N; X ² is CH or N; X ³ is CH or N; X ⁴ is CH or N; wherein X ¹ , X ² , one or both of X ³ and X ⁴ are N; A is CN; B is hetAr ¹ ; hetAr ¹ is a 5-membered heteroaryl ring with 1-3 ring nitrogen atoms, wherein the heteroaryl ring is viewed Cases are substituted by one or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl, hydroxyC1-C6 alkyl, fluoroC1-C6 alkyl, difluoroC1-C6 alkyl, trifluoroC1-C6 alkyl, Fluorine C1-C6 alkyl, cyano C1-C6 alkyl, (C1-C6 alkoxy) C1-C6 alkyl, (C1-C4 alkoxy) CH ₂ C(=O)-, (C1-C4 Alkoxy)C(=O)C1-C3alkyl, C3-C6cycloalkyl, (R ^a R ^b N)C1-C6 alkyl, (R ^a R ^b N)C(=O)C1-C6 Alkyl, (C1-C6 alkylSO ₂ )C1-C6 alkyl and 4-methoxybenzyl; R ^a and R ^b are independently H or C ₁ -C ₆ alkyl; D is hetCyc ¹ ; hetCyc ¹ is a 4-6 membered heterocyclic ring having 1-2 ring nitrogen atoms, wherein the heterocyclic ring is optionally substituted by one or more substituents independently selected from the group consisting of: C1-C3 alkyl, fluorine C1-C3 alkyl, difluoro C1-C3 alkyl, trifluoro C1-C3 alkyl and OH, or the heterocycle is substituted by a C3-C6 cycloalkylene ring, or the heterocycle is substituted by a side oxo; E is (w) Ar ² C(=O)-, (x) Ar ² C1-C6 alkyl-, (z) Ar ² (C1-C3 alkyl)C(=O)-, wherein the alkyl moiety is viewed as Occasionally substituted with one or two groups independently selected from the group consisting of: OH, C1-C6 alkyl (optionally substituted by 1-3 fluorine), hydroxyC1-C6 alkyl, C1-C6 alkoxy and R ^e R ^f N-, wherein R ^e and R ^f are independently H or C1-C6 alkyl, or R ^e and R ^f form a 5-6-membered nitrogen heterocyclic ring together with the nitrogen to which they are attached, depending on the circumstances having other ring heteroatoms selected from N and O, (cc) ^hetAr2 (C1-C3alkyl)C(=O)-, wherein the alkyl moiety is optionally one or two independently selected from the group consisting of Group substitution: OH, C1-C6 alkyl, hydroxy C1-C6 alkyl, C1-C6 alkoxy and R ^e R ^f N-, where R ^e and R ^f are independently H or C1-C6 alkane The group or ^Re and R ^f together with the nitrogen to which they are attached form a 5-6 membered nitrogen heterocyclic ring, which optionally has other ring heteroatoms selected from N and O, (dd) R ¹ R ² NC(=O)- , (oo) hetAr ² C1-C6 alkyl-, Ar ² is phenyl, which is optionally substituted by one or more substituents independently selected from the group consisting of: halogen, C1-C6 alkyl, C1- C6 alkoxy (optionally substituted by 1-3 fluorine), fluoro C1-C6 alkyl, difluoro C1-C6 alkyl, trifluoro C1-C6 alkyl, CN, with 1-2 independently selected from 5-6 membered heterocyclic ring of N and O ring heteroatoms and R ⁱ R ^j N-, wherein R ⁱ and R ^j are independently H or C1-C6 alkyl; hetAr ² is a 5-6 membered heteroaryl ring , which have 1-3 ring heteroatoms independently selected from N, O and S and are optionally substituted with one or more substituents independently selected from the group consisting of: halogen, C1-C6 alkyl, C1 -C6 alkoxy (substituted by 1-3 fluorine as appropriate), fluoro C1-C6 alkyl, difluoro C1-C6 alkyl, trifluoro C1-C6 alkyl, hydroxy C1-C6 alkyl, (C3- C6) cycloalkyl, (C1-C6 alkoxy) C1-C6 alkyl, CN, OH and R'R''N-, wherein R' and R'' are independently H or C1-C3 alkyl; R ¹ is H, C1-C6 alkyl or (C1-C6 alkoxy) C1-C6 alkyl; and R ² is H, C1-C6 alkyl (substituted by 1-3 fluorine as appropriate), (C1 -C6 alkoxy) C1-C6 alkyl (substituted by 1-3 fluorine as the case may be), hydroxyl C1-C6 alkyl (substituted by 1-3 fluorine as the case may be), C1-C6 alkoxy (as the case may be substituted by 1-3 fluorine substituted by 1-3 fluorine), (C1-C6 alkoxy)C(=O), hydroxyl C1-C6 alkoxy or (3-6C cycloalkyl)CH ₂ O.

In some embodiments, the RET inhibitor (eg, the first RET inhibitor or the second RET inhibitor) is selected from the group consisting of (S)-4-(6-(4-(2-hydroxy-3-benzene Propionyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3- Carbonitrile; 6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4-(2-(pyridin-2-yl)acetyl)piperazin-1-yl) Pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 2,2,2-trifluoroacetic acid 4-(6-(4-(2,6-difluorobenzoyl Base) piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 4-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl) -N,N-diethylpiperazine-1-carboxamide; 1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyridin-4-yl)pyridin-2-yl)-N-(2-methoxy-3-methylbutyl)piperidine-4-carboxamide; 4-(6-(4 -(2-(5-fluoropyridin-2-yl)acetyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyridine Azolo[1,5-a]pyridine-3-carbonitrile bis(2,2,2-trifluoroacetate); 4-(6-(4-(2,6-difluorobenzyl)piperazine -1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 4-(6 -(4-(2-methoxybenzyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyridine-3-carbonitrile; 6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4-(pyridin-2-ylmethyl)piperazine- 1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 4-(6-(4-((6-methoxypyridin-3-yl)methyl )piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; or Its pharmaceutically acceptable salt or solvate.

或其醫藥學上可接受之鹽或溶劑合物，其中： X¹ 、X² 、X³ 及X⁴ 獨立地為CH、CF、CCH₃ 或N，其中X¹ 、X² 、X³ 及X⁴ 中之零、一或兩者為N； A為H、CN、Cl、CH₃ -、CH₃ CH₂ -、環丙基、-CH₂ CN或-CH(CN)CH₃ ； B為 (a) 氫， (b) C1-C6烷基，其視情況經1-3個氟取代， (c) 羥基C2-C6烷基-，其中烷基部分視情況經1-3個氟或C3-C6亞環烷基環取代， (d) 二羥基C3-C6烷基-，其中烷基部分視情況經C3-C6亞環烷基環取代， (e) (C1-C6烷氧基)C1-C6烷基-，其視情況經1-3個氟取代， (f) (R¹ R² N)C1-C6烷基-，其中該烷基部分視情況經OH取代且其中R¹ 及R² 獨立地為H或C1-C6烷基(視情況經1-3個氟取代)； (g) hetAr¹ C1-C3烷基-，其中hetAr¹ 為具有1-3個獨立地選自N、O及S之環雜原子的5-6員雜芳基環且視情況經一或多個獨立地選擇之C1-C6烷基取代基取代； (h) (C3-C6環烷基)C1-C3烷基-，其中該環烷基視情況經OH取代， (i) (hetCyc^a )C1-C3烷基-， (j) hetCyc^a -， (k) C3-C6環烷基-，其中該環烷基視情況經OH取代， (l) (C1-C4烷基)C(=O)O-C1-C6烷基-，其中C1-C4烷基及C1-C6烷基部分中之每一者視情況且獨立地經1-3個氟取代，或 (m) (R¹ R² N)C(=O)C1-C6烷基-，其中R¹ 及R² 獨立地為H或C1-C6烷基(視情況經1-3個氟取代)； hetCyc^a -為4-6員雜環，其具有1-2個獨立地選自N及O之環雜原子且視情況經一或多個獨立地選自以下之取代基取代：OH、C1-C6烷基(視情況經1-3個氟取代)、羥基C1-C6烷基-、C1-C6烷氧基、(C1-C6烷基)C(=O)-、(C1-C6烷氧基)C1-C6烷基-及氟，或其中hetCyc^a 經側氧基取代； 環D為(i)具有兩個環氮原子之飽和4-7員雜環；(ii)具有兩個環氮原子且視情況具有第三環雜原子(其為氧)之7-8員飽和橋連雜環；(iii)具有兩個環氮原子之飽和7-11員螺雜環；或(iv)具有兩個環氮原子之飽和9-10員雙環稠合雜環，其中該等環中之每一者視情況經以下取代：(a)一至四個獨立地選自以下之基團：鹵素、OH、視情況經1-3個氟取代之C1-C3烷基或視情況經1-3個氟取代之C1-C3烷氧基，(b)C3-C6亞環烷基環，或(c)側氧基； E為 (a) 氫， (b) C1-C6烷基，其視情況經1-3個氟取代， (c) (C1-C6烷氧基)C1-C6烷基-，其視情況經1-3個氟取代， (d) (C1-C6烷基)C(=O)-，其中該烷基部分視情況經1-3個氟或R^g R^h N-取代基取代，其中R^g 及R^h 獨立地為H或C1-C6烷基， (e) (羥基C2-C6烷基)C(=O)-，其視情況經1-3個氟取代， (f) (C1-C6烷氧基)C(=O)-， (g) (C3-C6環烷基)C(=O)-，其中該環烷基視情況經一或多個獨立地選自以下之取代基取代：C1-C6烷基、C1-C6烷氧基、OH及(C1-C6烷氧基)C1-C6烷基-，或該環烷基經具有1-3個獨立地選自N及O之環雜原子之5-6員雜芳基環取代， (h) Ar¹ C1-C6烷基-， (i) Ar¹ (C1-C6烷基)C(=O)-，其中該烷基部分視情況經OH、羥基C1-C6烷基-、C1-C6烷氧基、R^m Rⁿ N-或R^m Rⁿ N-CH₂ -取代，其中各R^m 及Rⁿ 獨立地為H或C1-C6烷基， (j) hetAr² C1-C6烷基-，其中該烷基部分視情況經1-3個氟取代， (k) hetAr² (C1-C6烷基)C(=O)-，其中該烷基部分視情況經OH、羥基C1-C6烷基-或C1-C6烷氧基取代， (l) hetAr² C(=O)-， (m) hetCyc¹ C(=O)-， (n) hetCyc¹ C1-C6烷基-， (o) R³ R⁴ NC(=O)-， (p) Ar¹ N(R³ )C(=O)-， (q) hetAr² N(R³ )C(=O)-， (r) (C1-C6 alkyl)SO₂ -，其中烷基部分視情況經1-3個氟取代， (s) Ar¹ SO₂ -， (t) hetAr² SO₂ -， (u ) N-(C1-C6烷基)吡啶酮基， (v) Ar¹ C(=O)-； (w) Ar¹ O-C(=O)-， (x) (C3-C6環烷基)(C1-C6烷基)C(=O)-， (y) (C3-C6環烷基)(C1-C6烷基)SO₂ -，其中烷基部分視情況經1-3個氟取代， (z) Ar¹ (C1-C6烷基)SO₂ -， (aa) hetCyc¹ -O-C(=O)-， (bb) hetCyc¹ CH₂ C(=O)-， (cc) hetAr² ，或 (dd) C3-C6環烷基； Ar¹ 為苯基，其視情況經一或多個獨立地選自由以下組成之群之取代基取代：鹵素、CN、C1-C6烷基(視情況經1-3個氟取代)、C1-C6烷氧基(視情況經1-3個氟取代)、R^e R^f N-，其中R^e 及R^f 獨立地為H、C1-C6烷基、(R^p R^q N)C1-C6烷氧基-，其中R^p 及R^q 獨立地為H或C1-C6烷基，及(hetAr^a )C1-C6烷基-，其中hetAr^a 為具有1-2個環氮原子之5-6員雜芳基環，或Ar¹ 為與具有1-2個獨立地選自N及O之環雜原子之5-6員雜環稠合之苯環； hetAr² 為具有1-3個獨立地選自N、O及S之環雜原子之5-6員雜芳基環或具有1-3個環氮原子之9-10員雙環雜芳基環，其中hetAr² 視情況經一或多個獨立地選自由以下組成之群之取代基取代：鹵素、CN、C1-C6烷基(視情況經1-3個氟取代)、C1-C6烷氧基(視情況經1-3個氟取代)、(C1-C6烷氧基)C1-C6烷基-(視情況經1-3個氟取代)、R^e R^f N-，其中R^e 及R^f 獨立地為H或C1-C6烷基、OH、(C1-C6烷氧基)C1-C6烷氧基-及C3-C6環烷基； hetCyc¹ 為具有1-2個獨立地選自N、O及S之環雜原子之4-6員飽和雜環，其中該雜環視情況經一或多個獨立地選自C1-C6烷氧基及鹵素之取代基取代； R³ 為H或C1-C6烷基；及 R⁴ 為C1-C6烷基。In some embodiments, the RET inhibitor (eg, a first RET inhibitor or a second RET inhibitor) is a compound of formula IV :

or a pharmaceutically acceptable salt or solvate thereof, wherein: X ¹ , X ² , X ³ and X ⁴ are independently CH, CF, CCH ₃ or N, wherein X ¹ , X ² , X ³ and X Zero, one or both of ⁴ are N; A is H, CN, Cl, CH ₃ -, CH ₃ CH ₂ -, cyclopropyl, -CH ₂ CN or -CH(CN)CH ₃ ; B is ( a) hydrogen, (b) C1-C6 alkyl, which is optionally substituted by 1-3 fluorines, (c) hydroxyC2-C6 alkyl-, wherein the alkyl moiety is optionally substituted by 1-3 fluorines or C3- C6 cycloalkylene ring substitution, (d) dihydroxy C3-C6 alkyl-, wherein the alkyl part is optionally substituted by C3-C6 cycloalkylene ring, (e) (C1-C6 alkoxy)C1- C6 alkyl-, which is optionally substituted by 1-3 fluorines, (f) (R ¹ R ² N) C1-C6 alkyl-, wherein the alkyl moiety is optionally substituted by OH and wherein R ¹ and R ² independently H or C1-C6 alkyl (substituted by 1-3 fluorine as appropriate); (g) hetAr ¹ C1-C3 alkyl-, wherein hetAr ¹ has 1-3 independently selected from N, O and a 5-6 membered heteroaryl ring of ring heteroatoms of S and optionally substituted with one or more independently selected C1-C6 alkyl substituents; (h) (C3-C6 cycloalkyl)C1-C3 Alkyl-, wherein the cycloalkyl is optionally substituted by OH, (i) (hetCyc ^a ) C1-C3 alkyl-, (j) hetCyc ^a- , (k) C3-C6 cycloalkyl-, wherein the ring Alkyl is optionally substituted with OH, (l) (C1-C4 alkyl)C(=O)O-C1-C6 alkyl-, wherein each of the C1-C4 alkyl and C1-C6 alkyl moieties Optionally and independently substituted by 1-3 fluorine, or (m) (R ¹ R ² N)C(=O)C1-C6 alkyl-, wherein R ¹ and R ² are independently H or C1-C6 Alkyl (optionally substituted by 1-3 fluorine); hetCyc ^a - is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O and optionally substituted by one or more Substituents independently selected from the following substituents: OH, C1-C6 alkyl (substituted by 1-3 fluorine as appropriate), hydroxyl C1-C6 alkyl-, C1-C6 alkoxy, (C1-C6 alkyl )C(=O)-, (C1-C6 alkoxy) C1-C6 alkyl-and fluorine, or wherein hetCyc ^a is substituted by a side oxygen group; Ring D is (i) a saturated 4 with two ring nitrogen atoms -7 membered heterocycle; (ii) 7-8 membered saturated bridged heterocycle having two ring nitrogen atoms and optionally a third ring heteroatom (which is oxygen); (iii) having two ring nitrogen atoms A saturated 7-11 membered spiroheterocycle; or (iv) a saturated 9-10 membered bicyclic fused heterocycle having two ring nitrogen atoms, wherein each of these rings is optionally substituted by: (a) one to Four groups independently selected from the following groups: halogen, OH, C1-C3 alkyl optionally substituted by 1-3 fluorine or C1-C3 alkoxy optionally substituted by 1-3 fluorine, (b ) C3-C6 cycloalkylene ring, or (c) side oxygen group; E is (a) hydrogen, (b) C1-C6 alkyl, which is optionally substituted by 1-3 fluorine, (c) (C1 -C6alkoxy)C1-C6alkyl-, which is optionally substituted by 1-3 fluorines, (d) (C1-C6alkyl)C(=O)-, wherein the alkyl moiety is optionally substituted by 1 -3 fluorine or R ^g R ^h N-substituents are substituted, wherein R ^g and R ^h are independently H or C1-C6 alkyl, (e) (hydroxyl C2-C6 alkyl) C (= O)-, It is optionally substituted by 1-3 fluorines, (f) (C1-C6 alkoxy) C(=O)-, (g) (C3-C6 cycloalkyl) C(=O)-, wherein the ring Alkyl is optionally substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, OH and (C1-C6 alkoxy)C1-C6 alkyl-, or The cycloalkyl is substituted with a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N and O, (h) Ar ¹ C1-C6 alkyl-, (i) Ar ¹ ( C1-C6 alkyl)C(=O)-, wherein the alkyl moiety is optionally modified by OH, hydroxyl C1-C6 alkyl-, C1-C6 alkoxy, R ^m R ⁿ N- or R ^m R ⁿ N -CH ₂ -substituted, wherein each R ^m and R ⁿ are independently H or C1-C6 alkyl, (j) hetAr ² C1-C6 alkyl-, wherein the alkyl moiety is optionally substituted by 1-3 fluorine , (k) hetAr ² (C1-C6 alkyl) C (=O)-, wherein the alkyl moiety is optionally substituted by OH, hydroxyl C1-C6 alkyl- or C1-C6 alkoxy, (l) hetAr ² C(=O)-, (m) hetCyc ¹ C(=O)-, (n) hetCyc ¹ C1-C6 alkyl-, (o) R ³ R ⁴ NC(=O)-, (p) Ar ¹ N(R ³ )C(=O)-, (q) hetAr ² N(R ³ )C(=O)-, (r) (C1-C6 alkyl)SO ₂ -, where the alkyl moiety is optionally 1-3 fluorine substitutions, (s) Ar ¹ SO ₂ -, (t) hetAr ² SO ₂ -, (u) N-(C1-C6 alkyl) pyridonyl, (v) Ar ¹ C(=O )-; (w) Ar ¹ OC(=O)-, (x) (C3-C6 cycloalkyl) (C1-C6 alkyl) C(=O)-, (y) (C3-C6 cycloalkyl )(C1-C6 alkyl)SO ₂ -, wherein the alkyl moiety is optionally substituted by 1-3 fluorines, (z) Ar ¹ (C1-C6 alkyl)SO ₂ -, (aa) hetCyc ¹ -OC( =O)-, (bb) hetCyc ¹ CH ₂ C(=O)-, (cc) hetAr ² , or (dd) C3-C6 cycloalkyl; Ar ¹ is phenyl, which optionally undergoes one or more Substituents independently selected from the group consisting of: halogen, CN, C1-C6 alkyl (optionally substituted by 1-3 fluorine), C1-C6 alkoxy (optionally substituted by 1-3 fluorine ), ^Re R ^f N-, wherein R ^e and R ^f are independently H, C1-C6 alkyl, (R ^p R ^q N) C1-C6 alkoxy-, wherein R ^p and R ^q are independently H or C1-C6 alkyl, and (hetAr ^a ) C1-C6 alkyl-, wherein hetAr ^a is a 5-6 membered heteroaryl ring with 1-2 ring nitrogen atoms, or Ar ¹ is and has 1- ² 5-6 membered heterocyclic fused benzene rings independently selected from N and O ring heteroatoms; A 6-membered heteroaryl ring or a 9-10 membered bicyclic heteroaryl ring having 1-3 ring nitrogen atoms, wherein hetAr is optionally substituted with ^one or more substituents independently selected from the group consisting of halogen , CN, C1-C6 alkyl (substituted by 1-3 fluorine as appropriate), C1-C6 alkoxy (substituted by 1-3 fluorine as appropriate), (C1-C6 alkoxy) C1-C6 alkane Base-(substituted by 1-3 fluorine as appropriate), R ^e R ^f N-, wherein R ^e and R ^f are independently H or C1-C6 alkyl, OH, (C1-C6 alkoxy) C1- C6 alkoxy- and C3-C6 cycloalkyl; hetCyc ¹ is a 4-6 membered saturated heterocyclic ring with 1-2 ring heteroatoms independently selected from N, O and S, wherein the heterocyclic ring is optionally modified by one or a plurality of substituents independently selected from C1-C6 alkoxy and halogen; R ³ is H or C1-C6 alkyl; and R ⁴ is C1-C6 alkyl.

或其醫藥學上可接受之鹽及溶劑合物，其中： X¹ 、X² 、X³ 及X⁴ 獨立地為CH或N，其中X¹ 、X² 、X³ 及X⁴ 中之零、一或兩者為N； A為CN； B為 (b) C1-C6烷基，其視情況經1-3個氟取代， (c) 羥基C2-C6烷基-，其中烷基部分視情況經1-3個氟或C3-C6亞環烷基環取代， (e) (C1-C6烷氧基)C1-C6烷基-，其視情況經1-3個氟取代， (f) (R¹ R² N)C1-C6烷基-，其中該烷基部分視情況經OH取代且其中R¹ 及R² 獨立地為H或C1-C6烷基(視情況經1-3個氟取代)； (g) hetAr¹ C1-C3烷基-，其中hetAr¹ 為具有1-3個獨立地選自N、O及S之環雜原子之5-6員雜芳基環且視情況經一或多個獨立地選擇之C1-C6烷基取代基取代；或 (i) (hetCyc^a )C1-C3烷基-， hetCyc^a -為4-6員雜環，其具有1-2個獨立地選自N及O之環雜原子且視情況經一或多個獨立地選自以下之取代基取代：OH、C1-C6烷基(視情況經1-3個氟取代)、羥基C1-C6烷基-、C1-C6烷氧基、(C1-C6烷基)C(=O)-、(C1-C6烷氧基)C1-C6烷基-及氟，或其中hetCyc^a 經側氧基取代； 環D為(i)飽和4-7員雜環，其具有兩個環氮原子，或(ii)飽和7-9員橋連雜環，其具有兩個環氮原子且視情況具有第三環雜原子(其為氧)，其中該等環中之每一者視情況經以下取代：(a)一至四個獨立地選自以下之基團：鹵素、OH、視情況經1-3個氟取代之C1-C3烷基，或視情況經1-3個氟取代之C1-C3烷氧基，(b) C3-C6亞環烷基環，或(c)側氧基； E為 (h) Ar¹ C1-C6烷基-， (j) hetAr² C1-C6烷基-，其中烷基部分視情況經1-3個氟取代，或 (l) hetAr² C(=O)-， Ar¹ 為苯基，其視情況經一或多個獨立地選自由以下組成之群之取代基取代：鹵素、CN、C1-C6烷基(視情況經1-3個氟取代)、C1-C6烷氧基(視情況經1-3個氟取代)、R^e R^f N-，其中R^e 及R^f 獨立地為H、C1-C6烷基、(R^p R^q N)C1-C6烷氧基-，其中R^p 及R^q 獨立地為H或C1-C6烷基，及(hetAr^a )C1-C6烷基-，其中hetAr^a 為具有1-2個環氮原子之5-6員雜芳基環，或Ar¹ 為與具有1-2個獨立地選自N及O之環雜原子之5-6員雜環稠合之苯環； hetAr² 為具有1-3個獨立地選自N、O及S之環雜原子之5-6員雜芳基環或具有1-3個環氮原子之9-10員雙環雜芳基環，其中hetAr² 視情況經一或多個獨立地選自由以下組成之群之取代基取代：鹵素、CN、C1-C6烷基(視情況經1-3個氟取代)、C1-C6烷氧基(視情況經1-3個氟取代)、(C1-C6烷氧基)C1-C6烷基-(視情況經1-3個氟取代)、R^e R^f N-，其中R^e 及R^f 獨立地為H或C1-C6烷基、OH、(C1-C6烷氧基)C1-C6烷氧基-及C3-C6環烷基。In some embodiments, the RET inhibitor (eg, a first RET inhibitor or a second RET inhibitor) is a compound of formula V :

or their pharmaceutically acceptable salts and solvates, wherein: X ¹ , X ² , X ³ and X ⁴ are independently CH or N, wherein X ¹ , X ² , X ³ and X ⁴ are zero, One or both are N; A is CN; B is (b) C1-C6 alkyl, which is optionally substituted by 1-3 fluorine, (c) hydroxy C2-C6 alkyl-, wherein the alkyl part is optionally Substituted by 1-3 fluorine or C3-C6 cycloalkylene ring, (e) (C1-C6 alkoxy) C1-C6 alkyl-, which is optionally substituted by 1-3 fluorine, (f) ( R ¹ R ² N) C1-C6 alkyl-, wherein the alkyl moiety is optionally substituted by OH and wherein R ¹ and R ² are independently H or C1-C6 alkyl (optionally substituted by 1-3 fluorine ); (g) hetAr ¹ C1-C3 alkyl-, wherein hetAr ¹ is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and optionally modified by one Or a plurality of independently selected C1-C6 alkyl substituents are substituted; or (i) (hetCyc ^a ) C1-C3 alkyl-, hetCyc ^a -is a 4-6 membered heterocyclic ring having 1-2 independently Ring heteroatoms selected from N and O and optionally substituted with one or more substituents independently selected from: OH, C1-C6 alkyl (optionally substituted with 1-3 fluorine), hydroxyl C1-C6 Alkyl-, C1-C6 alkoxy, (C1-C6 alkyl) C(=O)-, (C1-C6 alkoxy) C1-C6 alkyl- and fluorine, or where hetCyc ^a through side oxygen Substitution; Ring D is (i) a saturated 4-7 membered heterocyclic ring having two ring nitrogen atoms, or (ii) a saturated 7-9 membered bridged heterocyclic ring having two ring nitrogen atoms and optionally having a second Tricyclic heteroatoms (which are oxygen), wherein each of the rings is optionally substituted by: (a) one to four groups independently selected from: halogen, OH, optionally 1-3 C1-C3 alkyl substituted by fluorine, or C1-C3 alkoxy substituted by 1-3 fluorine as the case may be, (b) C3-C6 cycloalkylene ring, or (c) pendant oxy group; E is (h) Ar ¹ C1-C6 alkyl-, (j) hetAr ² C1-C6 alkyl-, wherein the alkyl moiety is optionally substituted with 1-3 fluorines, or (l) hetAr ² C(=O)- , Ar ^is phenyl optionally substituted by one or more substituents independently selected from the group consisting of: halogen, CN, C1-C6 alkyl (optionally substituted by 1-3 fluorines), C1 -C6 alkoxy (substituted by 1-3 fluorine as appropriate), R ^e R ^f N-, wherein R ^e and R ^f are independently H, C1-C6 alkyl, (R ^p R ^q N) C1- C6 alkoxy-, wherein R ^p and R ^q are independently H or C1-C6 alkyl, and (hetAr ^a ) C1-C6 alkyl-, wherein hetAr ^a is 5- with 1-2 ring nitrogen atoms 6-membered heteroaryl ring, or Ar ¹ is a benzene ring fused to a 5-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O; hetAr ² is a benzene ring having 1-3 independently A 5-6 membered heteroaryl ring of ring heteroatoms selected from N, O and S or a 9-10 membered bicyclic heteroaryl ring with 1-3 ring nitrogen atoms, wherein hetAr ² is optionally replaced by one or more Substituents independently selected from the group consisting of: halogen, CN, C1-C6 alkyl (optionally substituted by 1-3 fluorine), C1-C6 alkoxy (optionally substituted by 1-3 fluorine substituted), (C1-C6 alkoxy) C1-C6 alkyl-(substituted by 1-3 fluorine as appropriate), R ^e R ^f N-, wherein R ^e and R ^f are independently H or C1-C6 Alkyl, OH, (C1-C6 alkoxy)C1-C6 alkoxy- and C3-C6 cycloalkyl.

In some embodiments, the RET inhibitor (eg, the first RET inhibitor or the second RET inhibitor) is selected from the group consisting of 4-(6-(4-benzylpiperazin-1-yl)pyridine- 3-yl)-6-(2-(N-morpholinyl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-(2-hydroxyethoxy)-4 -(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]hept-3-yl)pyridin-3-yl)pyridine Azolo[1,5-a]pyridine-3-carbonitrile; (R)-6-(2-hydroxypropoxy)-4-(6-(4-((6-methoxypyridine-3- Base)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-(2-hydroxy-2-methylpropoxy) -4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]hept-3-yl)pyridin-3-yl ) pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-(2-methoxyethoxy)-4-(6-(4-((6-methoxypyridine-3- Base)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-(2-hydroxy-2-methylpropoxy) -4-(6-(6-(6-methoxynicotinyl)-3,6-diazabicyclo[3.1.1]hept-3-yl)pyridin-3-yl)pyrazolo[ 1,5-a]pyridine-3-carbonitrile; 6-(2-(dimethylamino)ethoxy)-4-(6-(6-((6-methoxypyridin-3-yl )methyl)-3,6-diazabicyclo[3.1.1]hept-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 4-( 6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]hept-3-yl)pyridin-3-yl)-6- (2-(N-morpholinyl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile; 4-(6-(6-((6-methoxypyridine-3- Base) methyl)-3,6-diazabicyclo[3.1.1]hept-3-yl)pyridin-3-yl)-6-((1-methyl-1H-imidazol-4-yl)methyl Oxy)pyrazolo[1,5-a]pyridine-3-carbonitrile; and 6-ethoxy-4-(5-(6-((5-fluoro-6-methoxypyridine-3- base)methyl)-3,6-diazabicyclo[3.1.1]hept-3-yl)pyrazin-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; or Its pharmaceutically acceptable salt or solvate.

或其醫藥學上可接受之鹽或溶劑合物，其中： X¹ 、X² 、X³ 及X⁴ 獨立地為CH、CCH₃ 、CF或N，其中X¹ 、X² 、X³ 及X⁴ 中之零、一或兩者為N； A為H、CN、Cl、甲基、乙基或環丙基； B為： (a) 氫， (b) C1-C6烷基，其視情況經1-3個氟取代， (c) 羥基C2-C6烷基-，其中烷基部分視情況經C3-C6亞環烷基環取代， (d) 二羥基C3-C6烷基-，其中烷基部分視情況經C3-C6亞環烷基環取代， (e) (C1-C6烷氧基)C1-C6烷基-，其視情況經1-3個氟取代， (f) (R¹ R² N)C1-C6烷基-，其中R¹ 及R² 獨立地選自H、C1-C6烷基(視情況經1-3個氟取代)、(C1-C6烷氧基)C1-C6烷基-、(C1-C6烷基)C(=O)-及(C1-C6烷氧基)C(=O)-； (g) hetAr¹ C1-C3烷基-，其中hetAr¹ 為5-6員雜芳基環，其具有1-3個獨立地選自N、O及S之環雜原子且視情況經一或多個獨立地選擇之C1-C6烷基取代基取代； (h) (C3-C6環烷基)C1-C3烷基-，其中該環烷基視情況經OH取代， (i) (hetCyc^a )C1-C3烷基-， (j) hetCyc^a ， (k) (R¹ R² N)C(=O)C1-C6烷基-，其中R¹ 及R² 獨立地選自H及C1-C6烷基； (l) (R¹ R² N)C(=O)-，其中R¹ 及R² 獨立地選自H及C1-C6烷基，或 (m) hetCyc^a C(=O)C1-C6烷基-； hetCyc^a 為4-6員雜環，其具有1-2個獨立地選自N及O之環雜原子且視情況經一或多個獨立地選自以下之取代基取代：OH、C1-C6烷基(視情況經1-3個氟取代)、羥基C1-C6烷基、鹵素、(C1-C6烷基)C(=O)-、C1-C6烷氧基、側氧基及(C1-C6烷氧基)C(=O)-； 環D為(i)飽和單環4-7員雜環，其具有一個環雜原子(其為氮)，(ii)飽和7-8員橋連雜環，其具有一個環雜原子(其為氮)，或(iii)飽和7-11員螺雜環系統，其具有一個環雜原子(其為氮)； 各R^a 獨立地為C1-C6烷基(視情況經1-3個氟取代)、羥基C1-C6烷基或(C1-C6烷氧基)C1-C6烷基-； R^b 為(a)羥基，(b)環丙基，(c) hetCyc^b CH₂ -，(d) Rⁱ R^j NC(=O)CH₂ OCH₂ -，其中Rⁱ 及R^j 獨立地為H或C1-C6烷基，(e) R^c R^d N-，(f) R^c R^d NCH₂ -，(g) C1-C6烷氧基-，(h) (C1-C4烷基)-C(=O)NH-，其中該烷基部分視情況經hetCyc^b 、hetAr^a 、C1-C6烷氧基-或R'R"N-取代，或該烷基部分視情況經兩個獨立地選自R'R"N-及OH之取代基取代，其中各R'及R"獨立地為氫或C1-C6烷基，(i) (R'R"N)C1-C6烷氧基(CH₂ )_n -，其中n為0或1且R'及R''獨立地為氫或C1-C6烷基，(j) hetCyc^b (C1-C3烷基)OCH₂ -，(k) hetCyc^b C(=O)NH-或(l) hetAr^a C(=O)NH-； hetCyc^b 為4-6員雜環、7-8員橋連雜環或7-10員螺雜環，各環具有1-2個獨立地選自N及O之環雜原子，其中hetCyc^b 視情況經一或多個獨立地選自OH、氟、C1-C6烷基(視情況經1-3個氟取代)、羥基C1-C6烷基-(視情況經1-3個氟取代)、(C1-C6烷氧基)C1-C6烷基-、(C1-C6烷氧基)C(=O)-、C1-C6烷氧基及R'R"N-之取代基取代，其中R'及R"獨立地為氫或C1-C6烷基； hetAr^a 係具有1-3個獨立地選自N、O及S之環雜原子之5-6員雜芳基環，其中hetAr^a 視情況經一或多個獨立地選自由以下組成之群之取代基取代：鹵素、CN、C1-C6烷基(視情況經1-3個氟取代)及C1-C6烷氧基(視情況經1-3個氟取代)， R^c 為氫或C1-C6烷基； R^d 為氫、C1-C6烷基(視情況經1-3個氟取代)、(C1-C6烷氧基)C(=O)-、羥基C1-C6烷基(視情況經1-3個氟取代)、(羥基C1-C6烷基)C(=O)-、(C1-C6烷基)C(=O)-、(R^k R^l N)C1-C6烷基-，其中R^k 及R^l 獨立地為H或C1-C6烷基、R^m Rⁿ NC(=O)C1-C6烷基-(其中R^m 及Rⁿ 獨立地為H或C1-C6烷基)、PhCH₂ -，其中苯基視情況經一或多個獨立地選自由以下組成之群之取代基取代：鹵素、CN、C1-C6烷基(視情況經1-3個氟取代)、C1-C6烷氧基(視情況經1-3個氟取代)、(C1-C6烷氧基)C1-C6烷基- (視情況經1-3個氟取代)、C3-C6環烷基、羥基C1-C6烷基、(C1-C6烷基)SO₂ -、R^e R^f N-及(R^e R^f N)C1-C6烷基-，其中各R^e 及R^f 獨立地為H或C1-C6烷基，(C1-C6烷氧基)C1-C6烷基-，或hetCyc^c ，其中hetCyc^c 為4-6員雜環，其具有選自N及O之環雜原子且視情況經C1-C6烷基取代； n為0、1、2、3、4、5或6； m為0或1； E為： (a) 氫， (b) 羥基， (c) C1-C6烷基，其視情況經1-3個氟取代， (d) Ar¹ C1-C6烷基-，其中該烷基部分視情況經1-3個氟取代， (e) hetAr² C1-C6烷基-， (f) (C1-C6烷氧基)C1-C6烷氧基-， (g) Ar¹ O-， (h) hetAr² -O-， (i) Ar¹ NR^g -，其中R^g 為H或C1-C6烷基， (j) hetAr² NR^g -，其中R^g 為H或C1-C6烷基， (k) R³ C(=O)NR^g -，其中R^g 為H或C1-C6烷基， (l) Ar¹ C(=O)NR^g -，其中R^g 為H或C1-C6烷基， (m) hetAr² C(=O)NR^g (CH₂ )_p -，其中p為0或1且R^g 為H或C1-C6烷基， (n) R⁴ R⁵ NC(=O)-， (o) Ar¹ NR^g C(=O)-，其中R^g 為H或C1-C6烷基， (p) hetAr² NR^g C(=O)-，其中R^g 為H或C1-C6烷基， (q) Ar¹ (C1-C6烷基)C(=O)-，其中該烷基部分視情況經OH、羥基(C1-C6烷基)、C1-C6烷氧基或NH₂ 取代， (r) hetCyc⁵ C(=O)-， (s) R⁴ R⁵ NC(=O)NR^g -，其中R^g 為H或C1-C6烷基，或 (t) (C1-C6烷基)SO₂ -， (u) Ar¹ (C1-C6 alkyl)C(=O)NR^g -，其中R^g 為H或C1-C6烷基， (v) hetAr⁴ C(=O)NR^g -，其中R^g 為H或C1-C6烷基， (w) hetAr² -S(=O)-， (x) (C3-C6環烷基)CH₂ SO₂ -， (y) Ar¹ (C1-C6烷基)SO₂ -， (z) hetAr² SO₂ -， (aa) Ar¹ ， (bb) hetAr² ， (cc) hetCyc⁵ ， (dd) C1-C6烷氧基， (ee) Ar¹ (C1-C6烷基)-O-， (ff) hetAr² (C1-C6烷基)-O-， (gg) hetAr² -O-C1-C6烷基-， (hh) Ar¹ (C1-C6烷基)NR^g -，其中R^g 為H或C1-C6烷基， (ii) hetAr² -S-， (jj) Ar² SO₂ NR^g (CH₂ )_p -，其中p為0或1且R^g 為H或C1-C6烷基， (kk) (C1-C6烷氧基)C(=O)-， (ll) (C1-C6烷基)NR^g C(=O)O-，其中R^g 為H或C1-C6烷基， (mm) (C1-C6烷基)NR^g SO₂ -，其中R^g 為H或C1-C6烷基， (nn) hetCyc⁵ C(=O)NR^g -，其中R^g 為H或C1-C6烷基， (oo) Q-NR^h (C1-C3烷基)C(=O)NR^g -，其中R^g 及R^h 獨立地為H或C1-C6烷基且Q為H、C1-C6烷基或(C1-C6烷基)OC(=O)-， (pp)

，其中R^g 及R^h 獨立地為H或C1-C6烷基，Q為H、C1-C6烷基或(C1-C6烷基)OC(=O)-且r為1、2、3或4， (qq)

，其中R^g 及R^h 獨立地為H或C1-C6烷基且Q為H、C1-C6烷基或(C1-C6烷基)OC(=O)-， (rr)

，其中R^g 為H或C1-C6烷基且Q為H、C1-C6烷基或(C1-C6烷基)OC(=O)-，或 (ss) R^g R^h N-，其中R^g 及R^h 獨立地為H或C1-C6烷基， (tt) (C3-C6環烷基)C(=O)NR^g -，其中環烷基視情況且獨立地經一或多個鹵素取代， (uu) (C1-C6烷基)C(=O)NR^g CH₂ -，其中R^g 為H或C1-C6烷基，或 (vv) C1-C6烷基)SO₂ NR^g -，其中R^g 為H或C1-C6烷基； Ar¹ 為苯基，其視情況經一或多個獨立地選自由以下組成之群之取代基取代：鹵素、CN、C1-C6烷基(視情況經1-3個氟取代)、C1-C6烷氧基(視情況經1-3個氟取代)、(C1-C6烷氧基)C1-C6烷基-(視情況經1-3個氟取代)、C3-C6環烷基、羥基C1-C6烷基、(C1-C6烷基)SO₂ -、R^e R^f N-及(R^e R^f N)C1-C6烷基-，其中各R^e 及R^f 獨立地為H或C1-C6烷基； hetAr² 為具有1-3個獨立地選自N、O及S之環雜原子之5-6員雜芳基環，或具有1-2個環氮原子之9-10員雙環雜芳基，其中hetAr² 視情況經一或多個獨立地選自由以下組成之群之取代基取代：鹵素、CN、C1-C6烷基(視情況經1-3個氟取代)、C1-C6烷氧基(視情況經1-3個氟取代)、(C1-C6烷氧基)C1-C6烷基- (視情況經1-3個氟取代)及羥基C1-C6烷氧基-； hetCyc⁵ 為具有1-2個獨立地選自N、O及S之環雜原子之4-6員飽和雜環，其中該雜環視情況經一或多個獨立地選自C1-C6烷氧基及側氧基之取代基取代； R³ 為C1-C6烷基(視情況經1-3個氟取代)、羥基C1-C6烷基-、C1-C6烷氧基、C3-C6環烷基、(C3-C6環烷基)CH₂ -、(C3-C6環烷基)O-、(C3-C6環烷基)CH₂ O-、hetCyc⁷ O-、Ph-O-或(C1-C6烷氧基)C1-C6烷基-；其中該等C3-C6環烷基部分中之每一者視情況經C1-C6烷基(視情況經1-3個氟取代)、C1-C6烷氧基、OH或R'R''N-取代，其中R'及R''獨立地為氫或C1-C6烷基； R⁴ 為H或C1-C6烷基； R⁵ 為Ar² 、hetAr³ 、Ar² CH₂ -、hetCyc⁶ -CH₂ -、羥基C1-C6烷基-、(C3-C6環烷基)CH₂ -或C1-C6烷基，其視情況經1-3個氟取代； Ar² 為苯基，其視情況經一或多個獨立地選自由以下組成之群之取代基取代：鹵素、CN、C1-C6烷基(視情況經1-3個氟取代)、C1-C6烷氧基(視情況經1-3個氟取代)、(C1-C6烷氧基)C1-C6烷基- (視情況經1-3個氟取代)、C3-C6環烷基，及R^g R^h N-，其中各R^g 及R^h 獨立地為H或C1-C6烷基，或Ar² 為苯基，其與具有環氮原子之6員雜環稠合且視情況經C1-C6烷基取代； hetAr³ 為5-6員雜芳基環，其具有1-3個獨立地選自N、O及S之環雜原子且視情況經一或多個獨立地選自由以下組成之群之取代基取代：鹵素、CN、C1-C6烷基(視情況經1-3個氟取代)、C1-C6烷氧基(視情況經1-3個氟取代)及(C1-C6烷氧基)C1-C6烷基- (視情況經1-3個氟取代)； hetAr⁴ 為吡啶-4(1H)-酮基或吡啶-2(1H)-酮基，其視情況經一或多個獨立地選自C1-C6烷基及鹵素之取代基取代； hetCyc⁶ 為5-7員雜環，其具有1-3個獨立地選自N、O及S之環雜原子；及 hetCyc⁷ 為5-7員雜環，其具有1-3個獨立地選自N、O及S之環雜原子。In some embodiments, the RET inhibitor (eg, a first RET inhibitor or a second RET inhibitor) is a compound of Formula VI :

or a pharmaceutically acceptable salt or solvate thereof, wherein: X ¹ , X ² , X ³ and X ⁴ are independently CH, CCH ₃ , CF or N, wherein X ¹ , X ² , X ³ and X Zero, one or both of ⁴ are N; A is H, CN, Cl, methyl, ethyl or cyclopropyl; B is: (a) hydrogen, (b) C1-C6 alkyl, depending on the circumstances Substituted by 1-3 fluorine, (c) hydroxy C2-C6 alkyl-, wherein the alkyl part is optionally substituted by C3-C6 cycloalkylene ring, (d) dihydroxy C3-C6 alkyl-, wherein alkane The base moiety is optionally substituted by a C3-C6 cycloalkylene ring, (e) (C1-C6 alkoxy)C1-C6 alkyl-, which is optionally substituted by 1-3 fluorines, (f) (R ¹ R ² N) C1-C6 alkyl-, wherein R ¹ and R ² are independently selected from H, C1-C6 alkyl (substituted by 1-3 fluorine as appropriate), (C1-C6 alkoxy) C1- C6 alkyl-, (C1-C6 alkyl) C (=O)- and (C1-C6 alkoxy) C (=O)-; (g) hetAr ¹ C1-C3 alkyl-, wherein hetAr ¹ is A 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and optionally substituted by one or more independently selected C1-C6 alkyl substituents; ( h) (C3-C6cycloalkyl)C1-C3alkyl-, wherein the cycloalkyl is optionally substituted by OH, (i) (hetCyc ^a )C1-C3 alkyl-, (j) hetCyc ^a , (k ) (R ¹ R ² N) C (=O) C1-C6 alkyl-, wherein R ¹ and R ² are independently selected from H and C1-C6 alkyl; (l) (R ¹ R ² N) C ( =O)-, wherein R ¹ and R ² are independently selected from H and C1-C6 alkyl, or (m) hetCyc ^a C(=O)C1-C6 alkyl-; hetCyc ^a is a 4-6 membered heterocycle , which has 1-2 ring heteroatoms independently selected from N and O and optionally substituted with one or more substituents independently selected from: OH, C1-C6 alkyl (optionally via 1-3 fluorine substituted), hydroxyl C1-C6 alkyl, halogen, (C1-C6 alkyl) C (= O) -, C1-C6 alkoxy, side oxygen and (C1-C6 alkoxy) C (= O)-; Ring D is (i) a saturated monocyclic 4-7 membered heterocycle having one ring heteroatom (which is nitrogen), (ii) a saturated 7-8 membered bridged heterocycle having one ring heterocycle atom (which is nitrogen), or (iii) a saturated 7-11 membered spiro heterocyclic ring system having one ring heteroatom (which is nitrogen); each R ^a is independently C1-C6 alkyl (optionally via 1- 3 fluorine substituted), hydroxyl C1-C6 alkyl or (C1-C6 alkoxy) C1-C6 alkyl-; R ^b is (a) hydroxyl, (b) cyclopropyl, (c) hetCyc ^b CH ₂ -, (d) R ⁱ R ^j NC(=O)CH ₂ OCH ₂ -, wherein R ⁱ and R ^j are independently H or C1-C6 alkyl, (e) R ^c R ^d N-, (f) R ^c R ^d NCH ₂ -, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl) -C (= O) NH-, wherein the alkyl moiety is optionally hetCyc ^b , hetAr ^a , C1-C6 alkoxy- or R'R"N-substituted, or the alkyl moiety is optionally substituted by two substituents independently selected from R'R"N- and OH, wherein each R' and R" is independently hydrogen or C1-C6 alkyl, (i) (R'R"N)C1-C6 alkoxy (CH ₂ ) _n -, wherein n is 0 or 1 and R' and R'' are independently Ground is hydrogen or C1-C6 alkyl, (j) hetCyc ^b (C1-C3 alkyl) OCH ₂ -, (k) hetCyc ^b C (= O) NH- or (l) hetAr ^a C (= O) NH -; hetCyc ^b is a 4-6 membered heterocyclic ring, a 7-8 membered bridged heterocyclic ring or a 7-10 membered spiro heterocyclic ring, each ring has 1-2 ring heteroatoms independently selected from N and O, wherein hetCyc ^b optionally with one or more independently selected from OH, fluorine, C1-C6 alkyl (optionally substituted by 1-3 fluorine), hydroxyl C1-C6 alkyl- (optionally substituted by 1-3 fluorine ), (C1-C6 alkoxy) C1-C6 alkyl-, (C1-C6 alkoxy) C(=O)-, C1-C6 alkoxy and R'R"N-substituent substitution, wherein R' and R" are independently hydrogen or C1-C6 alkyl; hetAr ^is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S, wherein hetAr ^a is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluorines) and C1-C6 alkoxy (optionally substituted by 1-3 fluorine), R ^c is hydrogen or C1-C6 alkyl; R ^d is hydrogen, C1-C6 alkyl (substituted by 1-3 fluorine as appropriate), (C1-C6 alkoxy )C(=O)-, hydroxy C1-C6 alkyl (substituted by 1-3 fluorine as appropriate), (hydroxy C1-C6 alkyl) C(=O)-, (C1-C6 alkyl) C( =O)-, (R ^k R ^l N) C1-C6 alkyl-, wherein R ^k and R ^l are independently H or C1-C6 alkyl, R ^m R ⁿ NC (=O) C1-C6 alkyl -(where R ^m and R ⁿ are independently H or C1-C6 alkyl), PhCH ₂ -, wherein phenyl is optionally substituted by one or more substituents independently selected from the group consisting of: halogen, CN , C1-C6 alkyl (substituted by 1-3 fluorine as the case may be), C1-C6 alkoxy (substituted by 1-3 fluorine as the case may be), (C1-C6 alkoxy) C1-C6 alkyl- (optionally substituted by 1-3 fluorine), C3-C6 cycloalkyl, hydroxy C1-C6 alkyl, (C1-C6 alkyl) SO ₂ -, R ^e R ^f N- and (R ^e R ^f N ) C1-C6 alkyl-, wherein each R ^e and R ^f are independently H or C1-C6 alkyl, (C1-C6 alkoxy) C1-C6 alkyl-, or hetCyc ^c , wherein hetCyc ^c is 4 -6-membered heterocycle having ring heteroatoms selected from N and O optionally substituted by C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; E is: (a) hydrogen, (b) hydroxyl, (c) C1-C6 alkyl, optionally substituted by 1-3 fluorine, (d) Ar ¹ C1-C6 alkyl-, wherein the alkyl moiety Optionally substituted by 1-3 fluorine, (e) hetAr ² C1-C6 alkyl-, (f) (C1-C6 alkoxy) C1-C6 alkoxy-, (g) Ar ¹ O-, ( h) hetAr ² -O-, (i) Ar ^{NR g} -, wherein R ^g is H or C1-C6 alkyl, (j) hetAr ² NR ^g -, wherein R ^g is H or C1-C6 alkyl, (k) R ³ C(=O)NR ^g -, wherein R ^g is H or C1-C6 alkyl, (l) Ar ¹ C(=O)NR ^g -, wherein R ^g is H or C1-C6 alkane base, (m) hetAr ² C(=O)NR ^g (CH ₂ ) _p -, wherein p is 0 or 1 and R ^g is H or C1-C6 alkyl, (n) R ⁴ R ⁵ NC(=O )-, (o) Ar ¹ NR ^g C(=O)-, wherein R ^g is H or C1-C6 alkyl, (p) hetAr ² NR ^g C(=O)-, wherein R ^g is H or C1 -C6 alkyl, (q) Ar ¹ (C1-C6 alkyl) C (=O)-, wherein the alkyl moiety is optionally modified by OH, hydroxyl (C1-C6 alkyl), C1-C6 alkoxy or NH ₂ substitution, (r) hetCyc ⁵ C(=O)-, (s) R ⁴ R ⁵ NC(=O)NR ^g -, wherein R ^g is H or C1-C6 alkyl, or (t) (C1 -C6 alkyl)SO ₂ -, (u) Ar ¹ (C1-C6 alkyl)C(=O)NR ^g -, wherein R ^g is H or C1-C6 alkyl, (v) hetAr ⁴ C(=O )NR ^g -, wherein R ^g is H or C1-C6 alkyl, (w) hetAr ² -S(=O)-, (x) (C3-C6 cycloalkyl) CH ₂ SO ₂ -, (y) Ar ¹ (C1-C6 alkyl) SO ₂ -, (z) hetAr ² SO ₂ -, (aa) Ar ¹ , (bb) hetAr ² , (cc) hetCyc ⁵ , (dd) C1-C6 alkoxy, (ee) Ar ¹ (C1-C6 alkyl)-O-, (ff) hetAr ² (C1-C6 alkyl)-O-, (gg) hetAr ^2- O-C1-C6 alkyl-, (hh) Ar ¹ (C1-C6 alkyl) NR ^g -, wherein R ^g is H or C1-C6 alkyl, (ii) hetAr ² -S-, (jj) Ar ² SO ₂ NR ^g (CH ₂ ) _p -, Wherein p is 0 or 1 and R ^g is H or C1-C6 alkyl, (kk) (C1-C6 alkoxy) C (=O)-, (ll) (C1-C6 alkyl) NR ^g C ( =O)O-, where R ^g is H or C1-C6 alkyl, (mm) (C1-C6 alkyl) NR ^g SO ₂ -, where R ^g is H or C1-C6 alkyl, (nn) hetCyc ⁵ C(=O)NR ^g -, wherein R ^g is H or C1-C6 alkyl, (oo) Q-NR ^h (C1-C3 alkyl) C(=O)NR ^g -, wherein R ^g and R ^h is independently H or C1-C6 alkyl and Q is H, C1-C6 alkyl or (C1-C6 alkyl)OC(=O)-, (pp)

, wherein R ^g and R ^h are independently H or C1-C6 alkyl, Q is H, C1-C6 alkyl or (C1-C6 alkyl) OC (=O)- and r is 1, 2, 3 or 4, (qq)

, wherein R ^g and R ^h are independently H or C1-C6 alkyl and Q is H, C1-C6 alkyl or (C1-C6 alkyl) OC(=O)-, (rr)

, wherein R ^g is H or C1-C6 alkyl and Q is H, C1-C6 alkyl or (C1-C6 alkyl) OC(=O)-, or (ss) R ^g R ^h N-, wherein R ^g and R ^h are independently H or C1-C6 alkyl, (tt) (C3-C6 cycloalkyl) C (= O) NR ^g -, wherein cycloalkyl optionally and independently through one or more halogen Substituted, (uu) (C1-C6 alkyl) C (= O) NR ^g CH ₂ -, wherein R ^g is H or C1-C6 alkyl, or (vv) C1-C6 alkyl) SO ₂ NR ^g - , wherein R ^g is H or C1-C6 alkyl; Ar ^is phenyl, which is optionally substituted by one or more substituents independently selected from the group consisting of: halogen, CN, C1-C6 alkyl ( substituted by 1-3 fluorine as the case may be), C1-C6 alkoxy (substituted by 1-3 fluorine as the case may be), (C1-C6 alkoxy) C1-C6 alkyl- (by 1-3 fluorine as the case may be fluorine substituted), C3-C6 cycloalkyl, hydroxyl C1-C6 alkyl, (C1-C6 alkyl) SO ₂ -, R ^e R ^f N- and (R ^e R ^f N) C1-C6 alkyl- , wherein each R ^e and R ^f are independently H or C1-C6 alkyl; ^hetAr2 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S, Or a 9-10 membered bicyclic heteroaryl with ^1-2 ring nitrogen atoms, wherein hetAr is optionally substituted by one or more substituents independently selected from the group consisting of: halogen, CN, C1-C6 alkane Group (optionally substituted by 1-3 fluorine), C1-C6 alkoxy (optionally substituted by 1-3 fluorine), (C1-C6 alkoxy) C1-C6 alkyl- (optionally substituted by 1 -3 fluorine substituted) and hydroxyl C1-C6 alkoxyl group-; hetCyc ⁵ is a 4-6 membered saturated heterocyclic ring with 1-2 ring heteroatoms independently selected from N, O and S, wherein the heterocyclic ring is In some cases, it is substituted by one or more substituents independently selected from C1-C6 alkoxy and side oxy groups; ^R3 is C1-C6 alkyl (substituted by 1-3 fluorine as appropriate), hydroxy C1-C6 alkane -, C1-C6 alkoxy, C3-C6 cycloalkyl, (C3-C6 cycloalkyl) CH ₂ -, (C3-C6 cycloalkyl) O-, (C3-C6 cycloalkyl) CH ₂ O-, hetCyc ⁷ O-, Ph-O- or (C1-C6 alkoxy) C1-C6 alkyl-; wherein each of these C3-C6 cycloalkyl moieties is optionally modified by C1-C6 alkane (optionally substituted by 1-3 fluorine), C1-C6 alkoxy, OH or R'R''N-substituted, wherein R' and R'' are independently hydrogen or C1-C6 alkyl; R ⁴ is H or C1-C6 alkyl; R ⁵ is Ar ² , hetAr ³ , Ar ² CH ₂ -, hetCyc ⁶ -CH ₂ -, hydroxyl C1-C6 alkyl-, (C3-C6 cycloalkyl) CH ₂ - or C1-C6 alkyl, which is optionally substituted by 1-3 fluorine; Ar ² is phenyl, which is optionally substituted by one or more substituents independently selected from the group consisting of: halogen, CN, C1-C6 alkyl (substituted by 1-3 fluorine as appropriate), C1-C6 alkoxy (substituted by 1-3 fluorine as appropriate), (C1-C6 alkoxy) C1-C6 alkyl- ( Optionally substituted by 1-3 fluorine), C3-C6 cycloalkyl, and R ^g R ^h N-, wherein each R ^g and R ^h are independently H or C1-C6 alkyl, or Ar ² is phenyl , which is fused to a 6-membered heterocyclic ring having a ring nitrogen atom and optionally substituted by C1-C6 alkyl; hetAr ³ is a 5-6 membered heteroaryl ring having 1-3 independently selected from N, O and ring heteroatoms of S and optionally substituted by one or more substituents independently selected from the group consisting of: halogen, CN, C1-C6 alkyl (optionally substituted by 1-3 fluorine), C1- C6 alkoxy (substituted by 1-3 fluorine as appropriate) and (C1-C6 alkoxy) C1-C6 alkyl- (substituted by 1-3 fluorine as appropriate); hetAr ⁴ is pyridine-4 (1H )-keto or pyridin-2(1H)-one, optionally substituted by one or more substituents independently selected from C1-C6 alkyl and halogen; hetCyc ⁶ is a 5-7 membered heterocycle, which having 1-3 ring heteroatoms independently selected from N, O, and S; and hetCyc ⁷ is a 5-7 membered heterocycle having 1-3 ring heteroatoms independently selected from N, O, and S.

或其醫藥學上可接受之鹽或溶劑合物，其中： X¹ 、X² 、X³ 及X⁴ 獨立地為CH或N，其中X¹ 、X² 、X³ 及X⁴ 中之零、一或兩者為N； A為CN； B為： (b) C1-C6烷基，其視情況經1-3個氟取代， (c) 羥基C2-C6烷基-，其中烷基部分視情況經C3-C6亞環烷基環取代，或 (i) (hetCyc^a )C1-C3烷基-； hetCyc^a 為4-6員雜環，其具有1-2個獨立地選自N及O之環雜原子且視情況經一或多個獨立地選自以下之取代基取代：OH、C1-C6烷基(視情況經1-3個氟取代)、羥基C1-C6烷基、鹵素、(C1-C6烷基)C(=O)-、C1-C6烷氧基、側氧基及(C1-C6烷氧基)C(=O)-； 環D為飽和單環4-7員雜環，其具有一個環雜原子，該環雜原子為氮； 各R^a 獨立地為C1-C6烷基(視情況經1-3個氟取代)； R^b 為(a) 羥基； n為0或1； m為0或1； E為： (e) hetAr² C1-C6烷基-， (h) hetAr² -O-， (k) R³ C(=O)NR^g -，其中R^g 為H或C1-C6烷基， (l) Ar¹ C(=O)NR^g -，其中R^g 為H或C1-C6烷基，或 (m) hetAr² C(=O)NR^g (CH₂ )_p -，其中P為0或1且R^g 為H或C1-C6烷基； Ar¹ 為苯基，其視情況經一或多個獨立地選自由以下組成之群之取代基取代：鹵素、CN、C1-C6烷基(視情況經1-3個氟取代)、C1-C6烷氧基(視情況經1-3個氟取代)、(C1-C6烷氧基)C1-C6烷基-(視情況經1-3個氟取代)、C3-C6環烷基、羥基C1-C6烷基、(C1-C6烷基)SO₂ -、R^e R^f N-及(R^e R^f N)C1-C6烷基-，其中各R^e 及R^f 獨立地為H或C1-C6烷基； hetAr² 為具有1-3個獨立地選自N、O及S之環雜原子之5-6員雜芳基環，或具有1-2個環氮原子之9-10員雙環雜芳基，其中hetAr² 視情況經一或多個獨立地選自由以下組成之群之取代基取代：鹵素、CN、C1-C6烷基(視情況經1-3個氟取代)、C1-C6烷氧基(視情況經1-3個氟取代)、(C1-C6烷氧基)C1-C6烷基- (視情況經1-3個氟取代)及羥基C1-C6烷氧基-；及 R³ 為C1-C6烷基(視情況經1-3個氟取代)、羥基C1-C6烷基-、C1-C6烷氧基、C3-C6環烷基、(C3-C6環烷基)CH₂ -、(C3-C6環烷基)O-、(C3-C6環烷基)CH₂ O-、hetCyc⁷ O-、Ph-O-或(C1-C6烷氧基)C1-C6烷基-；其中該等C3-C6環烷基部分中之每一者視情況經C1-C6烷基(視情況經1-3個氟取代)、C1-C6烷氧基、OH或R'R''N-取代，其中R'及R''獨立地為氫或C1-C6烷基。In some embodiments, the RET inhibitor (eg, a first RET inhibitor or a second RET inhibitor) is a compound of Formula VII :

or a pharmaceutically acceptable salt or solvate thereof, wherein: X ¹ , X ² , X ³ and X ⁴ are independently CH or N, wherein X ¹ , X ² , X ³ and X ⁴ are zero, One or both are N; A is CN; B is: (b) C1-C6 alkyl, optionally substituted by 1-3 fluorine, (c) hydroxy C2-C6 alkyl-, wherein the alkyl moiety is optionally Cases are substituted by a C3-C6 cycloalkylene ring, or (i) (hetCyc ^a ) C1-C3 alkyl-; hetCyc ^a is a 4-6 membered heterocyclic ring having 1-2 independently selected from N and O and optionally substituted by one or more substituents independently selected from: OH, C1-C6 alkyl (optionally substituted by 1-3 fluorine), hydroxyC1-C6 alkyl, halogen, (C1-C6 alkyl) C(=O)-, C1-C6 alkoxy, pendant oxy and (C1-C6 alkoxy) C(=O)-; Ring D is a saturated monocyclic 4-7 member Heterocyclic ring, which has a ring heteroatom, the ring heteroatom is nitrogen; each R ^a is independently C1-C6 alkyl (substituted by 1-3 fluorine as appropriate); R ^b is (a) hydroxyl; n is 0 or 1; m is 0 or 1; E is: (e) hetAr ² C1-C6 alkyl-, (h) hetAr ² -O-, (k) R ³ C(=O)NR ^g -, wherein R ^g is H or C1-C6 alkyl, (l) Ar ¹ C(=O)NR ^g -, wherein R ^g is H or C1-C6 alkyl, or (m) hetAr ² C(=O)NR ^g ( CH ₂ ) _p -, wherein P is 0 or 1 and R ^g is H or C1-C6 alkyl; Ar ¹ is phenyl, which is optionally substituted by one or more substituents independently selected from the group consisting of : Halogen, CN, C1-C6 alkyl (substituted by 1-3 fluorine as the case may be), C1-C6 alkoxy (substituted by 1-3 fluorine as the case may be), (C1-C6 alkoxy) C1- C6 alkyl-(substituted by 1-3 fluorine as appropriate), C3-C6 cycloalkyl, hydroxyl C1-C6 alkyl, (C1-C6 alkyl)SO ₂ -, R ^e R ^f N- and (R ^e R ^f N) C1-C6 alkyl-, wherein each R ^e and R ^f are independently H or C1-C6 alkyl; hetAr ² is ring hetero with 1-3 independently selected from N, O and S Atomic 5-6 membered heteroaryl ring, or 9-10 membered bicyclic heteroaryl group having 1-2 ring nitrogen atoms, wherein hetAr ² is optionally substituted by one or more independently selected from the group consisting of Substitution: halogen, CN, C1-C6 alkyl (substituted by 1-3 fluorine as appropriate), C1-C6 alkoxy (substituted by 1-3 fluorine as appropriate), (C1-C6 alkoxy) C1-C6 alkyl- (substituted by 1-3 fluorine as appropriate) and hydroxyl C1-C6 alkoxy-; and ^R3 is C1-C6 alkyl (substituted by 1-3 fluorine as appropriate), hydroxyl C1 -C6 alkyl-, C1-C6 alkoxy, C3-C6 cycloalkyl, (C3-C6 cycloalkyl) CH ₂ -, (C3-C6 cycloalkyl) O-, (C3-C6 cycloalkyl )CH ₂ O-, hetCyc ⁷ O-, Ph-O-, or (C1-C6 alkoxy) C1-C6 alkyl-; wherein each of these C3-C6 cycloalkyl moieties is optionally modified by C1 -C6 alkyl (optionally substituted by 1-3 fluorine), C1-C6 alkoxy, OH or R'R''N-substituted, where R' and R'' are independently hydrogen or C1-C6 alkane base.

In some embodiments, the RET inhibitor (eg, the first RET inhibitor or the second RET inhibitor) is selected from the group consisting of: N-(1-(5-(3-cyano-6-(2-hydroxy -2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)benzamide; 6- Ethoxy-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile; 6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-(pyridin-2-yloxy)azetidin-1-yl)pyridine-3 -yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-((6-methoxy (Pyridazin-3-yl)oxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; Hydroxy-2-methylpropoxy)-4-(6-(3-(pyridin-2-yloxy)pyrrolidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a ]pyridine-3-carbonitrile; N-(1-(5-(3-cyano-6-((3-fluoro-1-methylazetidin-3-yl)methoxy)pyrazolo [1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-5-fluoro-2-methylbenzamide; 3-chloro-N -(1-(5-(3-cyano-6-((3-fluoro-1-methylazetidin-3-yl)methoxy)pyrazolo[1,5-a]pyridine- 4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)pyridinecarboxamide; N-((3S,4S)-1-(5-(3-cyano-6-ethane Oxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-hydroxypiperidin-4-yl)-3-methylbutanamide; 6-(2-hydroxy -2-methylpropoxy)-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1, 5-a]pyridine-3-carbonitrile; and 3-chloro-N-((3S,4S)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a ]pyridin-4-yl)pyrazin-2-yl)-3-hydroxypiperidin-4-yl)pyridinecarboxamide; or a pharmaceutically acceptable salt or solvate thereof.

Non-limiting examples of receptor tyrosine kinase (e.g., Trk) targeting therapeutics include afatinib, cabozantinib, cetuximab, crizotinib ), dabrafenib, entrectinib, erlotinib, gefitinib, imatinib, lapatinib, Lestaurtinib, nilotinib, pazopanib, panitumumab, pertuzumab, sunitinib, trastole Trastuzumab, 1-((3S,4R)-4-(3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4- Methyl-3-(2-methylpyrimidin-5-yl)-1-phenyl-1H-pyrazol-5-yl)urea, AG 879, AR-772, AR-786, AR-256, AR- 618, AZ-23, AZ623, DS-6051, Gö 6976, GNF-5837, GTx-186, GW 441756, LOXO-101, MGCD516, PLX7486, RXDX101, VM-902A, TPX-0005 and TSR-011. Other Trk-targeted therapeutics include those described in U.S. Patent Nos. 8,450,322, 8,513,263, 8,933,084, 8,791,123, 8,946,226, 8,450,322, 8,299,057, and 8,912,194; U.S. Publication Nos. 2016/0137654, 2015/0166564, 2015/0051222, 2015/0283132, and 2015/0306086; International Publication Nos. WO 2010/033941, WO 2010/048314, WO 2016/077841, WO 2011/146336, WO 2011/006074, WO 2010/033941, WO 2012/158413, WO 2014078454, WO 2014078417, WO 201407840 No. 8, WO 2014078378, WO 2014078372, WO 2014078331, WO 2014078328, WO 2014078325, WO 2014078323, WO 2014078322, WO 2015175788, WO 2009/013126, WO 2013 /174876, WO 2015/124697, WO 2010/058006, WO 2015/017533, WO 2015/112806, WO 2013/183578 and WO 2013/074518, all in full Incorporated herein by reference.

Additional examples of Trk inhibitors can be found in U.S. Patent No. 8,637,516, International Publication No. WO 2012/034091, U.S. Patent No. 9,102,671, International Publication No. WO 2012/116217, U.S. Publication No. 2010/0297115 , International Publication No. WO 2009/053442, U.S. Patent No. 8,642,035, International Publication No. WO 2009092049, U.S. Patent No. 8,691,221, International Publication No. WO2006131952, all of which are incorporated by reference in their entirety In this article. Exemplary Trk inhibitors include GNF-4256 described in Cancer Chemother. Pharmacol. 75(1):131-141, 2015; and ACS Med. Chem. Lett. 3(2):140-145, 2012 GNF-5837 (N-[3-[[2,3-dihydro-2-oxo-3-(1H-pyrrol-2-ylmethylene)-1H-indol-6-yl]amine yl]-4-methylphenyl]-N'-[2-fluoro-5-(trifluoromethyl)phenyl]-urea), each of which is incorporated herein by reference in its entirety.

Other examples of Trk inhibitors include those disclosed in U.S. Publication No. 2010/0152219, U.S. Patent No. 8,114,989, and International Publication No. WO 2006/123113, all of which are incorporated herein by reference in their entirety . Exemplary Trk inhibitors include AZ623 described in Cancer 117(6):1321-1391, 2011; AZD6918 described in Cancer Biol. Ther. 16(3):477-483, 2015; Cancer Chemother. Pharmacol. 70 AZ64 described in :477-486, 2012; AZ-23 ((S)-5-chloro-N2-(1-(5-fluoropyridine) described in Mol. Cancer Ther. 8:1818-1827 , 2009 -2-yl)ethyl)-N4-(5-isopropoxy-1H-pyrazol-3-yl)pyrimidine-2,4-diamine); and AZD7451; each of which is incorporated by reference in its entirety In this article.

Trk inhibitors may include inhibitors described in U.S. Patent Nos. 7,615,383; 7,384,632; 6,153,189; 6,027,927; 6,025,166; 5,910,574; Incorporated herein by reference.

Other examples of Trk inhibitors include CEP-751 described in Int. J. Cancer 72:672-679, 1997; CT327 described in Acta Derm. Venereol. 95:542-548, 2015; International Publication No. WO 2012/ Compounds described in US Patent No. 8,673,347 and International Publication No. WO 2007/022999; compounds described in US Patent No. 8,338,417; International Publication No. WO 2016/027754 compounds described in U.S. Patent No. 9,242,977; compounds described in U.S. Publication No. 2016/0000783; sunitinib (N-(2-diethylaminoethyl)-5-[(Z )-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide), such as PLoS One 9 : described in e95628, 2014; Compounds described in International Publication No. WO 2011/133637; Compounds described in U.S. Patent No. 8,637,256; Expert. Opin. Ther. Pat. 24(7):731-744, Compounds described in 2014; Compounds described in Expert Opin. Ther. Pat. 19(3):305-319, 2009; Imidazopyridazines substituted with (R)-2-phenylpyrrolidine, such as GNF-8625 , (R)-1-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-[2, 4'-bipyridin]-2'-yl)piperidin-4-ol, as described in ACS Med. Chem. Lett. 6(5):562-567, 2015; GTx-186 and other inhibitors, such as PLoS One 8(12):e83380, 2013 described; K252a ((9S-(9α,10β,12α))-2,3,9,10,11,12-hexahydro-10-hydroxy-10-( Methoxycarbonyl)-9-methyl-9,12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4 -i][1,6]benzodiazepine-1-one), as described in Mol. Cell Biochem. 339(1-2):201-213, 2010; 4-aminopyrazolylpyrimidine, For example AZ-23 (((S)-5-chloro-N2-(1-(5-fluoropyridin-2-yl)ethyl)-N4-(5-isopropoxy-1H-pyrazole-3- base) pyrimidine-2,4-diamine)) as described in J. Med. Chem. 51(15):4672-4684, 2008; PHA-739358 (danusertib) as described in Mol. Described in Cancer Ther. 6:3158, 2007; Gö 6976 (5,6,7,13-tetrahydro-13-methyl-5-oxo-12H-indolo[2,3-a]pyrrole [3,4-c]carbazole-12-propionitrile), as described in J. Neurochem. 72:919-924, 1999; GW441756 ((3Z)-3-[(1-methylindole- 3-yl)methylene]-1H-pyrrolo[3,2-b]pyridin-2-one), as described in IJAE 115:117, 2010; milciclib (PHA-848125AC), Described in J. Carcinog. 12:22, 2013; AG-879 ((2E)-3-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2- cyano-2-propenethioamide); altiratinib (N-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5 -difluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dimethylamide); cabozantinib (N-(4-((6,7-dimethoxyquinoline -4-yl)oxy)phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dimethylamide); letatinib ((5S,6S,8R)-6- Hydroxy-6-(hydroxymethyl)-5-methyl-7,8,14,15--tetrahydro-5H-16-oxo-4b,8a,14-triazol-5,8-methylenebis benzo[b,h]cyclooct[jkl]cyclopenta[e]-as-dicyclopentacene-13(6H)-one); dovatinib mono-2-hydroxyl Propionate hydrate (4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinoline-2(1H)- Ketone); Stetinib (N-(3-fluoro-4-((2-(5-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)thieno[ 3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dimethylamide); ONO-5390556; Regorafenib ( Hydrated 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]aminoformyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-methanol amide); and VSR-902A; all of the above references are incorporated herein by reference in their entirety.

The ability of a Trk inhibitor to act as a TrkA, TrkB, and/or Trk C inhibitor can be tested using the assays described in Examples A and B of US Patent No. 8,513,263, which is incorporated herein by reference.

In some embodiments, the receptor tyrosine kinase inhibitor is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR). For example, EGFR inhibitors may include osimertinib (meretinib, Tagrisso), erlotinib (Tarceva), gefitinib Gefitinib (Iressa), Cetuximab (Erbitux), Necitumumab (Portrazza), Neratinib (Lenin Nerlynx), lapatinib (Tykerb), panitumumab (Vectibix), and vandetanib (Caprelsa). In some embodiments, the EGFR inhibitor is osimertinib.

In some embodiments, signal transduction pathway inhibitors include Ras-Raf-MEK-ERK pathway inhibitors (such as binitinib, selumetinib, encorafenib, Sorafenib, trametinib, and vemurafenib), PI3K-Akt-mTOR-S6K pathway inhibitors (such as everolimus, rapamycin ), perifosine, temsirolimus), and other kinase inhibitors such as baricitinib, brigatinib, capmatinib, Danusertib, ibrutinib, milciclib, quercetin, regorafenib, ruxolitinib, semazanib ( semaxanib), AP32788, BLU285, BLU554, INCB39110, INCB40093, INCB50465, INCB52793, INCB54828, MGCD265, NMS-088, NMS-1286937, PF 477736 ((R)-amino-N-[5,6-dihydro -2 -(1-methyl-1H-pyrazol-4-yl)-6-oxo-1H pyrrolo[4,3,2-ef][2,3]benzodiazepine-8-yl] -cyclohexaneacetamide), PLX3397, PLX7486, PLX8394, PLX9486, PRN1008, PRN1371, RXDX103, RXDX106, RXDX108 and TG101209 (N-tert-butyl-3-(5-methyl-2-(4-( 4-methylpiperazin-1-yl)phenylamino)pyrimidin-4-ylamino)benzenesulfonamide).

Non-limiting examples of checkpoint inhibitors include ipilimumab, tremelimumab, nivolumab, pidilizumab, MPDL3208A, MEDI4736, MSB0010718C , BMS-936559, BMS-956559, BMS-935559 (MDX-1105), AMP-224 and pembrolizumab.

In some embodiments, the cytotoxic chemotherapeutic agent is selected from arsenic trioxide, bleomycin, cabazitaxel, capecitabine, carboplatin, cisplatin , cyclophosphamide, cytarabine, dacarbazine, daunorubicin, docetaxel, doxorubicin, etoposide (etoposide), fluorouracil, gemcitabine, irinotecan, lomustine, methotrexate, mitomycin C, oxali Platinum (oxaliplatin), paclitaxel (paclitaxel), pemetrexed (pemetrexed), temozolomide (temozolomide), and vincristine (vincristine).

Non-limiting examples of angiogenesis-targeted therapies include aflibercept and bevacizumab.

In some embodiments, other therapies or therapeutic agents may include histidyl-tRNA synthetase (HRS) polypeptides or expressible nucleotides encoding HRS polypeptides.

The term "immunotherapy" refers to agents that modulate the immune system. In some embodiments, immunotherapy increases the expression and/or activity of regulatory factors of the immune system. In some embodiments, immunotherapy reduces the expression and/or activity of regulatory factors of the immune system. In some embodiments, immunotherapy recruits and/or enhances the activity of immune cells.

In some embodiments, the immunotherapy is cellular immunotherapy (eg, receptive T cell therapy, dendritic cell therapy, natural killer cell therapy). In some embodiments, the cellular immunotherapy is sipuleucel-T (APC8015; Provenge™; Plosker (2011) Drugs 71(1): 101-108). In some embodiments, cellular immunotherapy comprises cells expressing a chimeric antigen receptor (CAR). In some embodiments, the cellular immunotherapy is CAR-T cell therapy. In some embodiments, the CAR-T cell therapy is tisagenlecleucel (Kymriah™).

In some embodiments, the immunotherapy is antibody therapy (eg, monoclonal antibodies, conjugated antibodies). In some embodiments, the antibody therapy is bevacizumab (Mvasti™, Avastin®), trastuzumab (Herceptin®), avelumab (Bavencio®) , rituximab (MabThera™, Rituxan®), edrecolomab (Panorex), daratumuab (Darzalex®), olaratumab (Lartruvo ™), ofatumumab (Arzerra®), alemtuzumab (Campath®), cetuximab (Erbitux®), oregovomab (oregovomab), Rizumab (Keytruda®), dinutiximab (Unituxin®), obinutuzumab (Gazyva®), tremelimumab (CP-675,206), Ramucirumab (Cyramza®), ublituximab (TG-1101), panitumumab (Vectibix®), elotuzumab (Empliciti ™), avelumab (Bavencio®), necitumumab (Portrazza™), cirmtuzumab (UC-961), ibritumomab ( Zevalin®), isatuximab (SAR650984), nimotuzumab, fresolimumab (GC1008), lirilumab (INN), Mo Mogamulizumab (Poteligeo®), ficlatuzumab (AV-299), denosumab (Xgeva®), ganitumab, excellent Rilumab, pidilizumab, or amatuximab.

In some embodiments, the immunotherapy is an antibody-drug conjugate. In some embodiments, the antibody-drug conjugate is gemtuzumab ozogamicin (Mylotarg™), inotuzumab ozogamicin (Besponsa®), Berento Brentuximab vedotin (Adcetris®), trastuzumab-matansine conjugate (TDM-1; Kadcyla®), mirvetuximab soravtansine (IMGN853 ) or anetumab ravtansine.

In some embodiments, the immunotherapy comprises blinatumomab (AMG103; Blincyto®) or midostaurin (Rydapt).

In some embodiments, immunotherapy includes toxins. In some embodiments, the immunotherapy is denileukin diftitox (Ontak®).

In some embodiments, the immunotherapy is cytokine therapy. In some embodiments, the interleukin therapy is interleukin 2 (IL-2) therapy, interferon alpha (IFN alpha), granulocyte colony stimulating factor (G-CSF) therapy, interleukin 12 (IL-12) therapy, interleukin 15 (IL-15) therapy, interleukin 7 (IL-7) therapy, or erythropoietin-alpha (EPO) therapy. In some embodiments, the IL-2 therapy is aldesleukin (Proleukin®). In some embodiments, the IFNα therapy is IntronA® (Roferon-A®). In some embodiments, the G-CSF therapy is filgrastim (Neupogen®).

In some embodiments, the immunotherapy is an immune checkpoint inhibitor. In some embodiments, immunotherapy includes one or more immune checkpoint inhibitors. In some embodiments, the immune checkpoint inhibitor is a CTLA-4 inhibitor, a PD-1 inhibitor, or a PD-L1 inhibitor. In some embodiments, the CTLA-4 inhibitor is ipilimumab (Yervoy®) or tremelimumab (CP-675,206). In some embodiments, the PD-1 inhibitor palivizumab (Keytruda®) or nivolumab (Opdivo®). In some embodiments, the PD-L1 inhibitor is atezolizumab (Tecentriq®), evelumab (Bavencio®), or durvalumab (Imfinzi™).

In some embodiments, the immunotherapy is mRNA-based immunotherapy. In some embodiments, the mRNA-based immunotherapy is CV9104 (see, eg, Rausch et al. (2014) Human Vaccin Immunother 10(11): 3146-52; and Kubler et al. (2015) J. Immunother Cancer 3:26).

In some embodiments, the immunotherapy is bacillus Calmette-Guerin (BCG) therapy.

In some embodiments, the immunotherapy is oncolytic virotherapy. In some embodiments, the oncolytic virotherapy is talimogene alherparepvec (T-VEC; Imlygic®).

In some embodiments, the immunotherapy is a cancer vaccine. In some embodiments, the cancer vaccine is a human papillomavirus (HPV) vaccine. In some embodiments, the HPV vaccine is Gardasil®, Gardasil9®, or Cervarix®. In some embodiments, the cancer vaccine is a hepatitis B virus (HBV) vaccine. In some embodiments, the HBV vaccine is Engerix-B®, Recombivax HB®, or GI-13020 (Tarmogen®). In some embodiments, the cancer vaccine is Twinrix® or Pediarix®. In some embodiments, the cancer vaccine is BiovaxID®, Oncophage®, GVAX, ADXS11-001, ALVAC-CEA, PROSTVAC®, Rindopepimut®, CimaVax-EGF, Lapuleucel-T (APC8024; Neuvenge ™), GRNVAC1, GRNVAC2, GRN-1201, Hepcortespenlisimut-L (Hepko-V5), DCVAX®, SCIB1, BMT CTN 1401, PrCa VBIR, PANVAC, ProstAtak®, DPX-Survivac or Wei Zipma-L (viagenpumatucel-L) (HS-110).

In some embodiments, the immunotherapy is a peptide vaccine. In some embodiments, the peptide vaccine is nelipepimut-S (E75) (NeuVax™), IMA901 or SurVaxM (SVN53-67). In some embodiments, the cancer vaccine is an immunogenic personal neoantigen vaccine (see, eg, Ott et al. (2017) Nature 547: 217-221; Sahin et al. (2017) Nature 547: 222-226). In some embodiments, the cancer vaccine is RGSH4K or NEO-PV-01. In some embodiments, the cancer vaccine is a DNA-based vaccine. In some embodiments, the DNA-based vaccine is a mammoglobulin-A DNA vaccine (see, eg, Kim et al. (2016) OncoImmunology 5(2):el069940).

In some embodiments, the immune targeting agent is selected from the group consisting of aldesleukin, interferon alpha-2b, ipilimumab, lambrolizumab, nivolumab, prednisone ) and Cypriency-T.

Non-limiting examples of radiation therapy include radioactive iodine therapy, external beam radiation, and radium-223 therapy.

Other kinase inhibitors include, for example, those described in U.S. Pat. No. 9,273,051; U.S. Publication No. US 2015/0018336; International Publication Nos. WO 2007/002325, WO 2007/002433, WO 2008/080001, WO 2008/079906, WO 2008/079903 No., WO 2008/079909, WO 2008/080015, WO 2009/007748, WO 2009/012283, WO 2009/143018, WO 2009/143024, WO 2009/014637 , WO 2009/152083, WO 2010/111527, WO 2012/109075, WO 2014/194127, WO 2015/112806, WO 2007/110344, WO 2009/071480, WO 2009/118411, WO 2010/031816, WO 2010/145998, WO 2011/092120, WO 2012/101032, WO 2012/139930, WO 2012/143248, WO 2012/152763, WO 2013/014039, WO 2013/102059, WO 2013/050448, WO 2013/050446, WO 2014/019908, WO 2014/072220, WO 2014/184069 and WO 2016/075224, both of which are incorporated herein by reference in their entirety.

Further examples of kinase inhibitors include inhibitors such as described in WO 2016/081450; WO 2016/022569; WO 2016/011141; WO 2016/011144; WO 2016/011147; WO 2015/191667; WO 2012/113774; WO 2015/191666; WO 2015/161277; WO 2015/161274; WO 2015/108992; WO 2015/061572; 2015/017528; WO/2015 /017533; WO 2014/160521; and WO 2014/011900, each of which is incorporated herein by reference in its entirety.

Other examples of kinase inhibitors include luminespib (AUY-922, NVP-AUY922) (5-(2,4-dihydroxy-5-isopropylphenyl)-N-ethyl-4- (4-(morpholinomethyl)phenyl)isoxazole-3-carboxamide) and damamod (doramapimod) (BIRB-796) (1-[5-tert-butyl-2-( 4-methylphenyl)pyrazol-3-yl]-3-[4-(2-morpholin-4-ylethoxy)naphthalen-1-yl]urea).

Therefore, this paper also provides a method of treating cancer, which comprises administering to a patient in need a pharmaceutical combination for treating cancer, which comprises (a) a compound of formula I or a pharmaceutically acceptable salt or solvate thereof; (b) other therapeutic agents, and (c) optionally at least one pharmaceutically acceptable carrier for simultaneous, separate or sequential use in the treatment of cancer, wherein the compound of formula I or its pharmaceutically acceptable carrier Amounts of the salt or solvate and other therapeutic agent are received to be jointly effective in treating cancer.

In some embodiments, the additional therapeutic agent comprises any of the therapies or therapeutic agents listed above as standard of care for a cancer having expression or activity or levels of the RET gene, RET protein, or either The disorder.

These other therapeutic agents may be administered as part of the same or separate dosage forms together with one or more doses of the compound of formula I or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition thereof, via the same or different administrations route, and/or by the same or a different schedule of administration, according to standard pharmaceutical practice known to those skilled in the art.

Also provided herein is (i) a pharmaceutical combination comprising (a) a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, (b) at least an additional therapeutic agent (such as any of the exemplary additional therapeutic agents described herein or known in the art), and (c) optionally at least one pharmaceutically acceptable carrier, which For simultaneous, separate or sequential use to treat cancer, wherein the compound of formula I or its pharmaceutically acceptable salt or solvate and other therapeutic agents are effective together in the treatment of cancer; (ii) pharmaceutical composition, It comprises such combinations; (iii) the use of such combinations for the manufacture of a medicament for the treatment of cancer; and (iv) a commercially available package or product comprising such combinations in a combined preparation for simultaneous , separate or sequential use; and methods of treating cancer in a patient in need thereof. In some embodiments, the patient is human. In some embodiments, the cancer is a RET-associated cancer. For example, RET-associated cancers have one or more RET inhibitor resistance mutations.

As used herein, the term "pharmaceutical combination" refers to a medical therapy produced by mixing or combining more than one active ingredient and includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that the compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, and at least one other therapeutic agent (eg, chemotherapeutic agent) are both administered to the patient simultaneously in a single composition or dosage form. The term "non-fixed combination" means that the compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, and at least one other therapeutic agent (eg, a chemotherapeutic agent) are formulated in separate compositions or dosage forms such that they can be Simultaneous, concurrent or sequential administration to a patient in need thereof under varying time constraints of intervention, wherein such administration provides effective amounts of two or more compounds in the patient. Such combinations are also suitable for combination therapy, eg administration of three or more active ingredients.

Therefore, this paper also provides a method of treating cancer, which comprises administering to a patient in need a pharmaceutical combination for treating cancer, which comprises (a) a compound of formula I or a pharmaceutically acceptable salt or solvate thereof; (b) other therapeutic agents, and (c) optionally at least one pharmaceutically acceptable carrier for simultaneous, separate or sequential use in the treatment of cancer, wherein the compound of formula I or its pharmaceutically acceptable carrier Amounts of the salt or solvate and other therapeutic agent are received to be jointly effective in treating cancer. In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, and the other therapeutic agent are administered simultaneously in separate dosage forms. In some embodiments, the compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, and other therapeutic agents are combined in a therapeutically effective amount, sequentially in any order in divided doses (eg, daily or intermittent doses) vote with. In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, and the other therapeutic agent are administered simultaneously in a combined dosage form. In some embodiments, the cancer is a RET-associated cancer. For example, RET-associated cancers have one or more RET inhibitor resistance mutations. In some embodiments, the additional therapeutic agent is crizotinib. In some embodiments, the other therapeutic agent is osimertinib. In some embodiments, one or more doses of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, are administered to the patient prior to administration of the pharmaceutical composition. In some embodiments, the cancer is lung cancer (eg, RET-associated lung cancer).

Also provided herein is a method of treating a RET-mediated disease or condition in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof substance or its pharmaceutical composition. In some embodiments, the disease or condition mediated by RET is a dysregulation of the expression or activity or level of the RET gene, RET kinase, or either. For example, dysregulation of the expression or activity or level of the RET gene, RET kinase, or either includes one or more RET inhibitor resistance mutations. A disease or condition mediated by RET can include any disease, disorder or condition that is directly or indirectly related to the expression or activity of RET, including overexpression and/or abnormal activity levels. In some embodiments, the disease is cancer (eg, RET-related cancer). In some embodiments, the cancer is any of the cancers described herein or a RET-related cancer. In some embodiments, the additional therapeutic agent is crizotinib. In some embodiments, the other therapeutic agent is osimertinib. In some embodiments, one or more doses of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, are administered to the patient prior to administration of the pharmaceutical composition. In some embodiments, the cancer is lung cancer (eg, RET-associated lung cancer).

Although the genetic basis of tumorigenesis can vary across cancer types, the cellular and molecular mechanisms required for metastasis appear to be similar for all solid tumor types. During the metastatic cascade, cancer cells lose their growth inhibitory response, undergo changes in cohesion and produce enzymes that degrade extracellular matrix components. This causes tumor cells to detach from the original tumor, infiltrate into the circulation via newly formed vessels, tumor cells migrate and extravasate to favorable distal sites where they can form colonies. Various genes have been identified as promoters or inhibitors of metastasis. For example, overexpression of glial cell-derived neurotrophic factor (GDNF) and its RET receptor tyrosine kinase has been associated with cancer proliferation and metastasis. See eg Zeng, Q. et al. J. Int. Med. Res. (2008) 36(4): 656-64.

Accordingly, also provided herein are methods for inhibiting, preventing, helping to prevent or reduce the symptoms of cancer metastasis in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable Accepted salts or solvates or pharmaceutical compositions thereof. Such methods can be used to treat one or more of the cancers described herein. See, eg, US Publication No. 2013/0029925; International Publication No. WO 2014/083567; and US Patent No. 8,568,998. See also eg Hezam K et al, Rev Neurosci 2018 Jan 26;29:93-98; Gao L et al, Pancreas 2015 Jan;44:134-143; Ding K et al, J Biol Chem 2014 Jun 6;289:16057-71; and Amit M et al., Oncogene 2017 Jun 8;36:3232-3239. In some embodiments, the cancer is a RET-associated cancer. In some embodiments, a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, is used in combination with other therapy or another therapeutic agent, including chemotherapeutic agents such as kinase inhibitors. For example, a first or second RET kinase inhibitor. In some embodiments, the additional therapeutic agent is crizotinib. In some embodiments, the other therapeutic agent is osimertinib. In some embodiments, one or more doses of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, are administered to the patient prior to administration of the pharmaceutical composition. In some embodiments, the cancer is lung cancer (eg, RET-associated lung cancer).

The term "metastasis" is a term known in the art and means the formation of other tumors (such as solid tumors) in an individual or patient at a site distant from the primary tumor, wherein the other tumors include the same or similar cancer cells.

Also provided are methods of reducing the risk of metastases or other metastases in patients with RET-associated cancers, comprising: selecting, identifying, or diagnosing patients with RET-associated cancers, and contributing to the selection, identification, or diagnosis of RET-associated cancers. A patient is administered a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof. Also provided is a method of reducing the risk of metastasis or other metastasis in a patient with a RET-associated cancer comprising administering to a patient with a RET-associated cancer a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof or solvates. The reduction in risk of developing metastases or other metastases in patients with RET-associated cancer can be compared to the risk of metastases or other metastases in patients prior to treatment, or to similar or identical risk in patients who have not received treatment or have received different treatment patients or groups of patients with RET-associated cancers. In some embodiments, the RET-associated cancer is a RET-associated cancer with one or more RET inhibitor resistance mutations. In some embodiments, the additional therapeutic agent is crizotinib. In some embodiments, the other therapeutic agent is osimertinib. In some embodiments, one or more doses of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, are administered to the patient prior to administration of the pharmaceutical composition. In some embodiments, the cancer is lung cancer (eg, RET-associated lung cancer).

The phrase "risk of developing metastases" means the risk of an individual or patient with a primary tumor developing other tumors (such as solid tumors) at a site distant from the primary tumor in the individual or patient during a set period of time , wherein the other tumor comprises the same or similar cancer cells as the primary tumor. Described herein are methods of reducing the risk of metastasis in an individual or patient with cancer.

The phrase "at risk of other metastases" means having a primary tumor and one or more other tumors at a site distant from the primary tumor (wherein the one or more other tumors include the same or similar cancer cells) will be at risk of developing one or more other tumors distant from the primary tumor, where the other tumors include the same or similar cancer cells as the primary tumor. This article describes methods to reduce the risk of other metastases occurring.

In some embodiments, the presence of one or more RET inhibitor resistance mutations in the tumor renders the tumor more resistant to treatment with the first RET inhibitor. Methods applicable when a RET inhibitor resistance mutation renders the tumor more resistant to treatment with a first RET inhibitor are described below. For example, provided herein are methods of treating an individual with cancer comprising: identifying an individual with cancer cells having one or more RET inhibitor resistance mutations; and administering a compound of formula I to the identified individual or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, is administered in combination with a first RET inhibitor. Also provided are methods of treating an individual identified as having cancer cells containing one or more RET inhibitor resistance mutations comprising administering to the individual a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, is administered in combination with a first RET inhibitor. In some embodiments, one or more RET inhibitor resistance mutations confer increased resistance to cancer cell or tumor to treatment with a first RET inhibitor. In some embodiments, the one or more RET inhibitor resistance mutations include one or more RET inhibitor resistance mutations listed in Tables 3 and 4. For example, one or more RET inhibitor resistance mutations can include a substitution at amino acid position 804, such as V804M, V804L, or V804E, or a substitution at amino acid position 810, such as G810S, G810R, G810C, G810A, G810V and G810D.

For example, provided herein are methods for treating RET-associated cancer in an individual in need of such treatment, the method comprising (a) detecting the expression of the RET gene, RET kinase, or either in a sample from the individual or a disorder of activity or level; and (b) administering to the individual a therapeutically effective amount of a first RET inhibitor, wherein the first RET inhibitor is selected from the group consisting of: alectinib, cabozantinib (cabozantinib), lenvatinib, nintedanib, ponatinib, regorafenib, sorafenib, sunitinib ), vandetanib, RXDX-105 (agerafenib), LOXO-292, BLU-667 ((1S,4R)-N-((S)-1-(6-(4 -Fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-((5-methyl-1H-pyrazole- 3-yl)amino)pyrimidin-2-yl)cyclohexane-1-carboxamide), BLU6864, DS-5010, GSK3179106, GSK3352589 and NMS-E668. In some embodiments, the methods further comprise (after (b)) (c) determining whether cancer cells in a sample obtained from the individual have at least one RET inhibitor resistance mutation; and (d) if the individual has For cancer cells with at least one RET inhibitor resistance mutation, a compound of formula I or a pharmaceutically acceptable salt or solvate thereof is administered to the individual as monotherapy or in combination with another anticancer agent; or (e ) if the individual has cancer cells that do not contain a RET inhibitor resistance mutation, then administering an additional dose of the first RET inhibitor of step (b) to the individual.

In some embodiments, provided herein are methods for treating a RET-associated cancer in an individual in need of such treatment, the method comprising (a) detecting the RET gene, RET kinase, or either of them in a sample from the individual and (b) administering to the individual a therapeutically effective amount of a first RET inhibitor, wherein the first RET inhibitor is selected from the group consisting of alectinib, cabozantinib, Lenvatinib, nintedanib, ponatinib, regorafenib, sorafenib, sunitinib, vandetanib, RXDX-105 (grafenib), LOXO-292, BLU- 667 ((1S,4R)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy- 4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexane-1-carboxamide), BLU6864, DS- 5010, GSK3179106, GSK3352589 and NMS-E668. In some embodiments, the methods further comprise (after (b)) (c) determining whether cancer cells in a sample obtained from the individual have at least one RET inhibitor resistance mutation; and (d) if the individual has For cancer cells with at least one RET inhibitor resistance mutation, a compound of formula I selected from Examples 1-10, Examples 11-20, Examples 21-34 is administered to the individual as monotherapy or in combination with another anticancer agent or a pharmaceutically acceptable salt or solvate thereof; or (e) if the individual has cancer cells that do not contain a RET inhibitor resistance mutation, then administering to the individual an additional dose of the first RET of step (b) Inhibitors.

In some embodiments, provided herein are methods for treating a RET-associated cancer in an individual in need of such treatment, the method comprising (a) detecting one or more fusion proteins of Table 1 in a sample from the individual and/or or one or more RET kinase protein point mutations/insertions/deletions of Table 2; and (b) administering to the individual a therapeutically effective amount of a first RET inhibitor, wherein the first RET inhibitor is selected from the group consisting of: Lentinib, Cabozantinib, Lenvatinib, Nintedanib, Ponatinib, Regorafenib, Sorafenib, Sunitinib, Vandetanib, RXDX-105 (Grafenib Nigeria), LOXO-292, BLU-667 ((1S,4R)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl Base)-1-methoxy-4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexane-1- Formamide), BLU6864, DS-5010, GSK3179106, GSK3352589 and NMS-E668. In some embodiments, the methods further comprise (after (b)) (c) determining whether the cancer cells in the sample obtained from the individual have at least one RET inhibitor resistance mutation of Table 3 or 4; and (d ) if the subject has cancer cells containing at least one RET inhibitor resistance mutation, administering to the subject selected from Examples 1-10, Examples 11-20, Example 21- A compound of formula I of 34, or a pharmaceutically acceptable salt or solvate thereof; or (e) if the individual has cancer cells that do not contain a RET inhibitor resistance mutation, the step of administering an additional dose to the individual (b ) the first RET inhibitor.

In some embodiments, provided herein are methods for treating a RET-associated cancer in an individual in need of such treatment, the method comprising (a) detecting the fusion protein KIF5B-RET in a sample from the individual; and (b) Administering to the individual a therapeutically effective amount of a first RET inhibitor, wherein the first RET inhibitor is selected from the group consisting of alectinib, cabozantinib, lenvatinib, nintedanib, purna Atinib, Legofenib, Sorafenib, Sunitinib, Vandetanib, RXDX-105 (Grafenib), LOXO-292, BLU-667 ((1S,4R)-N-(( S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-(( 5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexane-1-carboxamide), BLU6864, DS-5010, GSK3179106, GSK3352589 and NMS-E668. In some embodiments, the methods further comprise (after (b)) (c) determining whether the cancer cells in the sample obtained from the individual have the RET inhibitor resistance mutation V804M, G810S, or G810R; and (d) if The subject has cancer cells containing at least one RET inhibitor resistance mutation, and the subject is administered an agent selected from Examples 1-10, Examples 11-20, Examples 21-34 as monotherapy or in combination with another anticancer agent. A compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable salt or solvate thereof; or (e) if the individual has cancer cells that do not contain a RET inhibitor resistance mutation, An additional dose of the first RET inhibitor of step (b) is then administered to the individual.

As another example, provided herein are methods for treating RET-associated cancer in an individual in need of such treatment, the method comprising (a) detecting the RET gene, RET kinase, or either of them in a sample from the individual a disorder of expression or activity or level; and (b) administering to the subject a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) determining whether cancer cells in a sample obtained from the individual have at least one RET inhibitor resistance mutation; and (d) if the individual has For cancer cells with at least one RET inhibitor resistance mutation, a second therapeutic agent is administered to the subject as monotherapy or in combination with a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, wherein the second The therapeutic agent is selected from the group consisting of crizotinib and osimertinib; or (e) if the individual has cancer cells that do not contain a RET inhibitor resistance mutation, the step of (b) re-administering an additional dose to the individual A compound of formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, provided herein is a method of treating a RET-associated cancer in an individual in need of such treatment, the method comprising (a) detecting in a sample from the individual one or more fusion proteins of Table 1 and/or a or multiple RET kinase protein point mutations/insertions in Table 2; and (b) administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof to the individual. In some embodiments, the methods further comprise (after (b)) (c) determining whether the cancer cells in the sample obtained from the individual have at least one RET inhibitor resistance mutation of Table 3 or 4; and (d ) if the subject has cancer cells containing at least one RET inhibitor resistance mutation, administering a second therapeutic agent to the subject as monotherapy or in combination with a compound of formula I or a pharmaceutically acceptable salt or solvate thereof , wherein the second therapeutic agent is selected from the group consisting of crizotinib and osimertinib; or (e) administering an additional dose to the individual if the individual has cancer cells that do not contain a RET inhibitor resistance mutation The compound of formula I of step (b) or a pharmaceutically acceptable salt or solvate thereof. In some of the above embodiments, the RET-associated cancer is lung cancer.

As another example, provided herein are methods for treating RET-associated cancer in an individual in need of such treatment, the method comprising (a) detecting the RET gene, RET kinase, or either of them in a sample from the individual a disorder of expression or activity or level; and (b) administering to the individual a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) determining whether cancer cells in a sample obtained from the individual have at least one RET inhibitor resistance mutation; and (d) if the individual has Cancer cells with at least one RET inhibitor resistance mutation, the subject is then administered a second RET inhibitor as monotherapy or in combination with another anticancer agent, wherein the second RET inhibitor is selected from the group consisting of: Alectinib, cabozantinib, lenvatinib, nintedanib, ponatinib, regorafenib, sorafenib, sunitinib, vandetanib, RXDX-105 (Gra Finney), LOXO-292, BLU-667 ((1S,4R)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl) Ethyl)-1-methoxy-4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexane-1 -formamide), BLU6864, DS-5010, GSK3179106, GSK3352589, and NMS-E668; or (e) if the individual has cancer cells that do not contain a RET inhibitor resistance mutation, the step of readministering an additional dose to the individual ( b) a compound of formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, provided herein are methods for treating a RET-associated cancer in an individual in need of such treatment, the method comprising (a) detecting the RET gene, RET kinase, or either of them in a sample from the individual and (b) administering a therapeutically effective amount of a compound of formula I selected from examples 1-10, examples 11-20, examples 21-34 or a pharmaceutically acceptable salt thereof or solvates. In some embodiments, the methods further comprise (after (b)) (c) determining whether cancer cells in a sample obtained from the individual have at least one RET inhibitor resistance mutation; and (d) if the individual has Cancer cells with at least one RET inhibitor resistance mutation, the subject is then administered a second RET inhibitor as monotherapy or in combination with another anticancer agent, wherein the second RET inhibitor is selected from the group consisting of: Alectinib, cabozantinib, lenvatinib, nintedanib, ponatinib, regorafenib, sorafenib, sunitinib, vandetanib, RXDX-105 (Gra Finney), LOXO-292, BLU-667 ((1S,4R)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl) Ethyl)-1-methoxy-4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexane-1 -formamide), BLU6864, DS-5010, GSK3179106, GSK3352589, and NMS-E668; or (e) if the individual has cancer cells that do not contain a RET inhibitor resistance mutation, the step of readministering an additional dose to the individual ( b) a compound of formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, provided herein is a method of treating a RET-associated cancer in an individual in need of such treatment, the method comprising (a) detecting in a sample from the individual one or more fusion proteins of Table 1 and/or a or multiple RET kinase protein point mutations/insertions/deletions of Table 2; and (b) administering a therapeutically effective amount of a compound of formula I selected from examples 1-10, examples 11-20, examples 21-34 or a medicine thereof Pharmaceutically acceptable salts or solvates. In some embodiments, the methods further comprise (after (b)) (c) determining whether the cancer cells in the sample obtained from the individual have at least one RET inhibitor resistance mutation of Table 3 or 4; and (d ) if the individual has cancer cells containing at least one RET inhibitor resistance mutation, administering to the individual a second RET inhibitor, either as monotherapy or in combination with another anticancer agent, wherein the second RET inhibitor is selected from The group consisting of: alectinib, cabozantinib, lenvatinib, nintedanib, ponatinib, regorafenib, sorafenib, sunitinib, vandetanib, RXDX-105 (Grafenib), LOXO-292, BLU-667 ((1S,4R)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridine -3-yl)ethyl)-1-methoxy-4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl) Cyclohexane-1-carboxamide), BLU6864, DS-5010, GSK3179106, GSK3352589, and NMS-E668; or (e) readministering to an individual if the individual has cancer cells that do not contain a RET inhibitor resistance mutation An additional dose of the compound of formula I of step (b) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, provided herein are methods for treating a RET-associated cancer in an individual in need of such treatment, the method comprising (a) detecting the fusion protein KIF5B-RET in a sample from the individual; and (b) A therapeutically effective amount of a compound of formula I selected from Examples 1-10, Examples 11-20, Examples 21-34, or a pharmaceutically acceptable salt or solvate thereof is administered to the individual. In some embodiments, the methods further comprise (after (b)) (c) determining whether the cancer cells in the sample obtained from the individual have the RET inhibitor resistance mutation V804M, G810S, or G810R; and (d) if The individual has cancer cells containing at least one RET inhibitor resistance mutation, the individual is administered a second RET inhibitor as monotherapy or in combination with another anticancer agent, wherein the second RET inhibitor is selected from the group consisting of Group: alectinib, cabozantinib, lenvatinib, nintedanib, ponatinib, regorafenib, sorafenib, sunitinib, vandetanib, RXDX- 105 (grafenib), LOXO-292, BLU-667 ((1S,4R)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridine-3 -yl)ethyl)-1-methoxy-4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexyl alkane-1-carboxamide), BLU6864, DS-5010, GSK3179106, GSK3352589, and NMS-E668; or (e) readministering an additional dose to the individual if the individual has cancer cells that do not contain a RET inhibitor resistance mutation The compound of formula I of step (b) or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, the presence of one or more RET inhibitor resistance mutations in the tumor renders the tumor more resistant to treatment with the first RET inhibitor. Methods applicable when RET inhibitor resistance mutations render the tumor more resistant to treatment with a first RET inhibitor are described below. For example, provided herein are methods of treating an individual with cancer comprising: identifying an individual with cancer cells having one or more RET inhibitor resistance mutations; and administering a compound of formula I to the identified individual or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, is administered in combination with a first RET inhibitor. Also provided are methods of treating an individual identified as having cancer cells containing one or more RET inhibitor resistance mutations comprising administering to the individual a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, is administered in combination with a first RET inhibitor. In some embodiments, one or more RET inhibitor resistance mutations confer increased resistance to cancer cell or tumor to treatment with a first RET inhibitor. In some embodiments, the one or more RET inhibitor resistance mutations include one or more RET inhibitor resistance mutations listed in Tables 3 and 4. For example, one or more RET inhibitor resistance mutations can include a substitution at amino acid position 804, such as V804M, V804L, or V804E, or a substitution at amino acid position 810, such as G810S, G810R, G810C, G810A, G810V and G810D.

For example, provided herein are methods for treating RET-associated cancer in an individual in need of such treatment, the method comprising (a) detecting the expression of the RET gene, RET kinase, or either in a sample from the individual or a disorder of activity or level; and (b) administering to the individual a therapeutically effective amount of a first RET inhibitor, wherein the first RET inhibitor is selected from the group consisting of: ((S)-4-(6-( 4-(2-Hydroxy-3-phenylpropionyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[ 1,5-a]pyridine-3-carbonitrile; 6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4-(2-(pyridin-2-yl)ethyl Acyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 2,2,2-trifluoroacetic acid 4-(6-(4- (2,6-difluorobenzoyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5 -a]pyridine-3-carbonitrile; 4-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine- 4-yl)pyridin-2-yl)-N,N-diethylpiperazine-1-carboxamide; 1-(5-(3-cyano-6-(1-methyl-1H-pyrazole -4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-(2-methoxy-3-methylbutyl)piperidine-4-methyl Amide; 4-(6-(4-(2-(5-fluoropyridin-2-yl)acetyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl- 1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile bis(2,2,2-trifluoroacetate); 4-(6-(4-(2, 6-Difluorobenzyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine -3-carbonitrile; 4-(6-(4-(2-methoxybenzyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazole -4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4-(pyridine -2-ylmethyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 4-(6-(4-((6-methyl Oxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a] pyridine-3-carbonitrile; or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) assaying a sample obtained from an individual whether the cancer cells in the individual have at least one RET inhibitor resistance mutation; and (d) if the individual has cancer cells that contain at least one RET inhibitor resistance mutation, to The step of administering to the individual a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof; or (e) if the individual has cancer cells that do not contain a RET inhibitor resistance mutation, then administering an additional dose to the individual ( b) The first RET inhibitor.

In some embodiments, provided herein are methods for treating a RET-associated cancer in an individual in need of such treatment, the method comprising (a) detecting the RET gene, RET kinase, or either of them in a sample from the individual and (b) administering to the individual a therapeutically effective amount of a first RET inhibitor, wherein the first RET inhibitor is selected from the group consisting of: ((S)-4-(6 -(4-(2-Hydroxy-3-phenylpropionyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazole And[1,5-a]pyridine-3-carbonitrile; 6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4-(2-(pyridin-2-yl )Acetyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 2,2,2-trifluoroacetic acid 4-(6-( 4-(2,6-Difluorobenzoyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyridine-3-carbonitrile; 4-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a] Pyridin-4-yl)pyridin-2-yl)-N,N-diethylpiperazine-1-carboxamide; 1-(5-(3-cyano-6-(1-methyl-1H- Pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-(2-methoxy-3-methylbutyl)piperidine-4 -Formamide; 4-(6-(4-(2-(5-fluoropyridin-2-yl)acetyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl Base-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile bis(2,2,2-trifluoroacetate); 4-(6-(4-( 2,6-Difluorobenzyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a ]pyridine-3-carbonitrile; 4-(6-(4-(2-methoxybenzyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H- Pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4- (Pyridin-2-ylmethyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 4-(6-(4-((6 -Methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1, 5-a] pyridine-3-carbonitrile; or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) determining the obtained whether the cancer cells in the sample have at least one RET inhibitor resistance mutation; and (d) if the individual has cancer cells that contain at least one RET inhibitor resistance mutation, either as monotherapy or in combination with another anticancer agent Form administration is selected from the formula I compound of example 1-10, example 11-20, example 21-34 or its pharmaceutically acceptable salt or solvate to individual; Or (e) if individual has For cancer cells with drug resistance mutations, an additional dose of the first RET inhibitor of step (b) is then administered to the individual.

In some embodiments, provided herein are methods for treating a RET-associated cancer in an individual in need of such treatment, the method comprising (a) detecting one or more fusion proteins of Table 1 in a sample from the individual and/or or one or more RET kinase protein point mutations/insertions/deletions of Table 2; and (b) administering to the individual a therapeutically effective amount of a first RET inhibitor, wherein the first RET inhibitor is selected from the group consisting of: ( (S)-4-(6-(4-(2-Hydroxy-3-phenylpropionyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyridine Azol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4-( 2-(pyridin-2-yl)acetyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 2,2,2-tri Fluoroacetic acid 4-(6-(4-(2,6-difluorobenzoyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazole-4 -yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 4-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazole And[1,5-a]pyridin-4-yl)pyridin-2-yl)-N,N-diethylpiperazine-1-carboxamide; 1-(5-(3-cyano-6- (1-Methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-(2-methoxy-3-methyl butyl)piperidine-4-carboxamide; 4-(6-(4-(2-(5-fluoropyridin-2-yl)acetyl)piperazin-1-yl)pyridin-3-yl )-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile bis(2,2,2-trifluoroacetate); 4 -(6-(4-(2,6-difluorobenzyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyridine Azolo[1,5-a]pyridine-3-carbonitrile; 4-(6-(4-(2-methoxybenzyl)piperazin-1-yl)pyridin-3-yl)-6- (1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-(1-methyl-1H-pyrazol-4-yl)- 4-(6-(4-(pyridin-2-ylmethyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 4-( 6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazole-4- or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the methods further comprise (after (b) (c) determining whether cancer cells in a sample obtained from the individual have at least one RET inhibitor resistance mutation of Table 3 or 4; and (d) if the individual has cancer cells that contain at least one RET inhibitor resistance mutation, A compound of Formula I selected from Examples 1-10, Examples 11-20, Examples 21-34, or a pharmaceutically acceptable salt or solvate thereof is administered to the individual as monotherapy or in combination with another anticancer agent. or (e) if the individual has cancer cells that do not contain a RET inhibitor resistance mutation, then administering an additional dose of the first RET inhibitor of step (b) to the individual.

In some embodiments, provided herein are methods for treating RET-associated cancer in an individual in need of such treatment, the method comprising (a) detecting the fusion protein KIF5B-RET in a sample from the individual; and (b) Administering to the individual a therapeutically effective amount of a first RET inhibitor, wherein the first RET inhibitor is selected from the group consisting of: ((S)-4-(6-(4-(2-hydroxy-3-phenyl Propyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-methyl Nitrile; 6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4-(2-(pyridin-2-ylacetyl)piperazin-1-yl)pyridine- 3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 2,2,2-trifluoroacetic acid 4-(6-(4-(2,6-difluorobenzoyl) Piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 4- (5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N , N-diethylpiperazine-1-carboxamide; 1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5 -a]pyridin-4-yl)pyridin-2-yl)-N-(2-methoxy-3-methylbutyl)piperidine-4-carboxamide; 4-(6-(4-( 2-(5-fluoropyridin-2-yl)acetyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo [1,5-a]pyridine-3-carbonitrile bis(2,2,2-trifluoroacetate); 4-(6-(4-(2,6-difluorobenzyl)piperazine-1 -yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 4-(6-( 4-(2-methoxybenzyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5 -a] pyridine-3-carbonitrile; 6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4-(pyridin-2-ylmethyl)piperazine-1- yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 4-(6-(4-((6-methoxypyridin-3-yl)methyl)piper oxazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; or its medicine A pharmaceutically acceptable salt or solvate. In some embodiments, the methods further comprise (after (b)) (c) determining whether the cancer cells in the sample obtained from the individual have a RET inhibitor resistance mutation V804M, G810S, or G810R; and (d) if the individual has cancer cells containing at least one RET inhibitor resistance mutation, administering to the individual a group selected from Examples 1-10 as monotherapy or in combination with another anticancer agent. , the compound of formula I of example 11-20, example 21-34 or its pharmaceutically acceptable salt or solvate, or its pharmaceutically acceptable salt or solvate; Or (e) if individual has For cancer cells containing RET inhibitor resistance mutations, the individual is then administered an additional dose of the first RET inhibitor of step (b).

As another example, provided herein are methods for treating RET-associated cancer in an individual in need of such treatment, the method comprising (a) detecting the RET gene, RET kinase, or either of them in a sample from the individual a disorder of expression or activity or level; and (b) administering to the individual a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) determining whether cancer cells in a sample obtained from the individual have at least one RET inhibitor resistance mutation; and (d) if the individual has Cancer cells with at least one RET inhibitor resistance mutation, the subject is then administered a second RET inhibitor as monotherapy or in combination with another anticancer agent, wherein the second RET inhibitor is selected from the group consisting of: ((S)-4-(6-(4-(2-Hydroxy-3-phenylpropionyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H- Pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4- (2-(pyridin-2-yl)acetyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 2,2,2- 4-(6-(4-(2,6-difluorobenzoyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazole- 4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 4-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyridine Azolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N,N-diethylpiperazine-1-carboxamide; 1-(5-(3-cyano-6 -(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-(2-methoxy-3- Methylbutyl)piperidine-4-carboxamide; 4-(6-(4-(2-(5-fluoropyridin-2-yl)acetyl)piperazin-1-yl)pyridine-3- Base)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile bis(2,2,2-trifluoroacetate); 4-(6-(4-(2,6-difluorobenzyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl) Pyrazolo[1,5-a]pyridine-3-carbonitrile; 4-(6-(4-(2-methoxybenzyl)piperazin-1-yl)pyridin-3-yl)-6 -(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-(1-methyl-1H-pyrazol-4-yl) -4-(6-(4-(pyridin-2-ylmethyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 4- (6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazole-4 -yl) pyrazolo[1,5-a]pyridine-3-carbonitrile; or a pharmaceutically acceptable salt or solvate thereof; or (e) if the individual has cancer cells, then administer an additional dose of the compound of formula I of step (b) or a pharmaceutically acceptable salt or solvate thereof to the individual. In some embodiments, provided herein are for the treatment in need of such treatment A method for RET-associated cancer in an individual, the method comprising (a) detecting a disorder in the expression or activity or amount of the RET gene, RET kinase, or any of them in a sample from the individual; and (b) administering to the individual and a therapeutically effective amount of a compound of formula I selected from Examples 1-10, Examples 11-20, Examples 21-34 or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) determining whether cancer cells in a sample obtained from the individual have at least one RET inhibitor resistance mutation; and (d) if the individual has Cancer cells with at least one RET inhibitor resistance mutation, the subject is then administered a second RET inhibitor as monotherapy or in combination with another anticancer agent, wherein the second RET inhibitor is selected from the group consisting of: ((S)-4-(6-(4-(2-Hydroxy-3-phenylpropionyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H- Pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4- (2-(pyridin-2-yl)acetyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 2,2,2- 4-(6-(4-(2,6-difluorobenzoyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazole- 4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 4-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyridine Azolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N,N-diethylpiperazine-1-carboxamide; 1-(5-(3-cyano-6 -(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-(2-methoxy-3- Methylbutyl)piperidine-4-carboxamide; 4-(6-(4-(2-(5-fluoropyridin-2-yl)acetyl)piperazin-1-yl)pyridine-3- Base)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile bis(2,2,2-trifluoroacetate); 4-(6-(4-(2,6-difluorobenzyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl) Pyrazolo[1,5-a]pyridine-3-carbonitrile; 4-(6-(4-(2-methoxybenzyl)piperazin-1-yl)pyridin-3-yl)-6 -(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-(1-methyl-1H-pyrazol-4-yl) -4-(6-(4-(pyridin-2-ylmethyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 4- (6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazole-4 -yl) pyrazolo[1,5-a]pyridine-3-carbonitrile; or a pharmaceutically acceptable salt or solvate thereof; or (e) if the individual has cancer cells, then administer an additional dose of the compound of formula I of step (b) or a pharmaceutically acceptable salt or solvate thereof to the individual. In some embodiments, provided herein are for the treatment in need of such treatment A method for RET-associated cancer in an individual, the method comprising (a) detecting point mutations/insertions/deletions of one or more fusion proteins of Table 1 and/or one or more RET kinase proteins of Table 2 in a sample from an individual and (b) administering to the individual a therapeutically effective amount of a compound of formula I selected from Examples 1-10, Examples 11-20, Examples 21-34, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) determining whether the cancer cells in the sample obtained from the individual have at least one RET inhibitor resistance mutation of Table 3 or 4; and (d ) if the individual has cancer cells containing at least one RET inhibitor resistance mutation, administering to the individual a second RET inhibitor, either as monotherapy or in combination with another anticancer agent, wherein the second RET inhibitor is selected from The group consisting of: ((S)-4-(6-(4-(2-hydroxy-3-phenylpropionyl)piperazin-1-yl)pyridin-3-yl)-6-(1- Methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-(1-methyl-1H-pyrazol-4-yl)-4-( 6-(4-(2-(pyridin-2-yl)acetyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 2 ,2,2-Trifluoroacetic acid 4-(6-(4-(2,6-difluorobenzoyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl- 1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 4-(5-(3-cyano-6-(1-methyl-1H-pyrazole- 4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N,N-diethylpiperazine-1-carboxamide; 1-(5-(3 -cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-(2-methyl Oxy-3-methylbutyl)piperidine-4-carboxamide; 4-(6-(4-(2-(5-fluoropyridin-2-yl)acetyl)piperazin-1-yl )pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile bis(2,2,2-tri fluoroacetate); 4-(6-(4-(2,6-difluorobenzyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazole -4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 4-(6-(4-(2-methoxybenzyl)piperazin-1-yl)pyridine-3 -yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-(1-methyl-1H-pyrazole -4-yl)-4-(6-(4-(pyridin-2-ylmethyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3- Carbonitrile; 4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H -pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; or a pharmaceutically acceptable salt or solvate thereof; or (e) if the individual has For cancer cells with drug-resistant mutations, an additional dose of the compound of formula I of step (b) or a pharmaceutically acceptable salt or solvate thereof is readministered to the individual. In some embodiments, provided herein for use in A method of treating RET-associated cancer in an individual in need of such treatment, the method comprising (a) detecting the fusion protein KIF5B-RET in a sample from the individual; and (b) administering to the individual a therapeutically effective amount of 1-10, Examples 11-20, Examples 21-34 of the compounds of formula I or pharmaceutically acceptable salts or solvates thereof. In some embodiments, the methods further comprise (after (b)) (c) determining whether the cancer cells in the sample obtained from the individual have the RET inhibitor resistance mutation V804M, G810S, or G810R; and (d) if The individual has cancer cells containing at least one RET inhibitor resistance mutation, the individual is administered a second RET inhibitor as monotherapy or in combination with another anticancer agent, wherein the second RET inhibitor is selected from the group consisting of Group: ((S)-4-(6-(4-(2-hydroxy-3-phenylpropionyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl -1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-(1-methyl-1H-pyrazol-4-yl)-4-(6- (4-(2-(pyridin-2-yl)acetyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 2,2 ,2-Trifluoroacetic acid 4-(6-(4-(2,6-difluorobenzoyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H- Pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 4-(5-(3-cyano-6-(1-methyl-1H-pyrazole-4- Base) pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N,N-diethylpiperazine-1-carboxamide; 1-(5-(3-cyano Base-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-(2-methoxy -3-methylbutyl)piperidine-4-carboxamide; 4-(6-(4-(2-(5-fluoropyridin-2-yl)acetyl)piperazin-1-yl)pyridine -3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile bis(2,2,2-trifluoroacetic acid salt); 4-(6-(4-(2,6-difluorobenzyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazole-4 -yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 4-(6-(4-(2-methoxybenzyl)piperazin-1-yl)pyridin-3-yl )-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-(1-methyl-1H-pyrazole-4 -yl)-4-(6-(4-(pyridin-2-ylmethyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile ; 4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyridine Azol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; or a pharmaceutically acceptable salt or solvate thereof; or (e) if the subject has For cancer cells with sexual mutations, an additional dose of the compound of formula I in step (b) or a pharmaceutically acceptable salt or solvate thereof is administered to the individual.

In some embodiments, provided herein are methods for treating a RET-associated cancer in an individual in need of such treatment, the method comprising (a) detecting the RET gene, RET kinase, or either of them in a sample from the individual and (b) administering to the individual a therapeutically effective amount of a first RET inhibitor, wherein the first RET inhibitor is selected from the group consisting of 4-(6-(4-benzene Methylpiperazin-1-yl)pyridin-3-yl)-6-(2-(N-morpholinyl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile; 6 -(2-Hydroxyethoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane- 3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; (R)-6-(2-hydroxypropoxy)-4-(6-(4- ((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-(2 -Hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1] Hept-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-(2-methoxyethoxy)-4-(6-(4- ((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-(2 -Hydroxy-2-methylpropoxy)-4-(6-(6-(6-methoxynicotinyl)-3,6-diazabicyclo[3.1.1]hept-3-yl )pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-(2-(dimethylamino)ethoxy)-4-(6-(6-( (6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]hept-3-yl)pyridin-3-yl)pyrazolo[1,5-a ]pyridine-3-carbonitrile; 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]hept-3- Base) pyridin-3-yl)-6-(2-(N-morpholinyl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile; 4-(6-(6- ((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]hept-3-yl)pyridin-3-yl)-6-((1-methyl Base-1H-imidazol-4-yl)methoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile; and 6-ethoxy-4-(5-(6-((5- Fluoro-6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]hept-3-yl)pyrazin-2-yl)pyrazolo[1,5 -a] pyridine-3-carbonitrile; or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) determining whether cancer cells in a sample obtained from the individual have at least one RET inhibitor resistance mutation; and (d) if the individual has For cancer cells with at least one RET inhibitor resistance mutation, a compound of formula I or a pharmaceutically acceptable salt or solvate thereof is administered to the individual as monotherapy or in combination with another anticancer agent; or (e ) if the individual has cancer cells that do not contain a RET inhibitor resistance mutation, then administering an additional dose of the first RET inhibitor of step (b) to the individual.

In some embodiments, provided herein are methods for treating a RET-associated cancer in an individual in need of such treatment, the method comprising (a) detecting the RET gene, RET kinase, or either of them in a sample from the individual and (b) administering to the individual a therapeutically effective amount of a first RET inhibitor, wherein the first RET inhibitor is selected from the group consisting of 4-(6-(4-benzene Methylpiperazin-1-yl)pyridin-3-yl)-6-(2-(N-morpholinyl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile; 6 -(2-Hydroxyethoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane- 3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; (R)-6-(2-hydroxypropoxy)-4-(6-(4- ((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-(2 -Hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1] Hept-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-(2-methoxyethoxy)-4-(6-(4- ((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-(2 -Hydroxy-2-methylpropoxy)-4-(6-(6-(6-methoxynicotinyl)-3,6-diazabicyclo[3.1.1]hept-3-yl )pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-(2-(dimethylamino)ethoxy)-4-(6-(6-( (6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]hept-3-yl)pyridin-3-yl)pyrazolo[1,5-a ]pyridine-3-carbonitrile; 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]hept-3- Base) pyridin-3-yl)-6-(2-(N-morpholinyl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile; 4-(6-(6- ((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]hept-3-yl)pyridin-3-yl)-6-((1-methyl Base-1H-imidazol-4-yl)methoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile; and 6-ethoxy-4-(5-(6-((5- Fluoro-6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]hept-3-yl)pyrazin-2-yl)pyrazolo[1,5 -a] pyridine-3-carbonitrile; or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) determining whether cancer cells in a sample obtained from the individual have at least one RET inhibitor resistance mutation; and (d) if the individual has For cancer cells with at least one RET inhibitor resistance mutation, a compound of formula I selected from Examples 1-10, Examples 11-20, Examples 21-34 is administered to the individual as monotherapy or in combination with another anticancer agent or a pharmaceutically acceptable salt or solvate thereof; or (e) if the individual has cancer cells that do not contain a RET inhibitor resistance mutation, then administering to the individual an additional dose of the first RET of step (b) Inhibitor.

In some embodiments, provided herein are methods for treating a RET-associated cancer in an individual in need of such treatment, the method comprising (a) detecting one or more fusion proteins of Table 1 in a sample from the individual and/or or one or more RET kinase protein point mutations/insertions/deletions of Table 2; and (b) administering to the individual a therapeutically effective amount of a first RET inhibitor, wherein the first RET inhibitor is selected from the group consisting of: 4 -(6-(4-Benzylpiperazin-1-yl)pyridin-3-yl)-6-(2-(N-morpholinyl)ethoxy)pyrazolo[1,5-a] Pyridine-3-carbonitrile; 6-(2-hydroxyethoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazepine Bicyclo[3.1.1]hept-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; (R)-6-(2-hydroxypropoxy)- 4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3 -carbonitrile; 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-di Azabicyclo[3.1.1]hept-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-(2-methoxyethoxy)- 4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3 -formonitrile; 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-(6-methoxynicotinyl)-3,6-diazabicyclo[3.1 .1]hept-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-(2-(dimethylamino)ethoxy)-4 -(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]hept-3-yl)pyridin-3-yl)pyridine Azolo[1,5-a]pyridine-3-carbonitrile; 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[ 3.1.1] Hept-3-yl)pyridin-3-yl)-6-(2-(N-morpholinyl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile; 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]hept-3-yl)pyridin-3-yl) -6-((1-methyl-1H-imidazol-4-yl)methoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile; and 6-ethoxy-4-(5 -(6-((5-fluoro-6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]hept-3-yl)pyrazin-2-yl ) pyrazolo[1,5-a]pyridine-3-carbonitrile; or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) determining whether the cancer cells in the sample obtained from the individual have at least one RET inhibitor resistance mutation of Table 3 or 4; and (d ) if the subject has cancer cells containing at least one RET inhibitor resistance mutation, administering to the subject a group selected from Examples 1-10, Examples 11-20, Examples 21- as monotherapy or in combination with another anti-cancer agent A compound of formula I of 34, or a pharmaceutically acceptable salt or solvate thereof; or (e) if the individual has cancer cells that do not contain a RET inhibitor resistance mutation, the step of administering an additional dose to the individual (b ) the first RET inhibitor.

In some embodiments, provided herein are methods for treating a RET-associated cancer in an individual in need of such treatment, the method comprising (a) detecting the fusion protein KIF5B-RET in a sample from the individual; and (b) Administering to the individual a therapeutically effective amount of a first RET inhibitor, wherein the first RET inhibitor is selected from the group consisting of: 4-(6-(4-benzylpiperazin-1-yl)pyridin-3-yl )-6-(2-(N-morpholinyl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-(2-hydroxyethoxy)-4-(6 -(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]hept-3-yl)pyridin-3-yl)pyrazolo[ 1,5-a]pyridine-3-carbonitrile; (R)-6-(2-hydroxypropoxy)-4-(6-(4-((6-methoxypyridin-3-yl)methanol Base) piperazin-1-yl) pyridin-3-yl) pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-(2-hydroxy-2-methylpropoxy)-4- (6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]hept-3-yl)pyridin-3-yl)pyrazole And[1,5-a]pyridine-3-carbonitrile; 6-(2-methoxyethoxy)-4-(6-(4-((6-methoxypyridin-3-yl)methyl Base) piperazin-1-yl) pyridin-3-yl) pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-(2-hydroxy-2-methylpropoxy)-4- (6-(6-(6-methoxynicotinyl)-3,6-diazabicyclo[3.1.1]hept-3-yl)pyridin-3-yl)pyrazolo[1,5 -a] pyridine-3-carbonitrile; 6-(2-(dimethylamino)ethoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl )-3,6-diazabicyclo[3.1.1]hept-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 4-(6-( 6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]hept-3-yl)pyridin-3-yl)-6-(2- (N-morpholinyl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile; 4-(6-(6-((6-methoxypyridin-3-yl)methanol Base)-3,6-diazabicyclo[3.1.1]hept-3-yl)pyridin-3-yl)-6-((1-methyl-1H-imidazol-4-yl)methoxy) Pyrazolo[1,5-a]pyridine-3-carbonitrile; and 6-ethoxy-4-(5-(6-((5-fluoro-6-methoxypyridin-3-yl)methanol base)-3,6-diazabicyclo[3.1.1]hept-3-yl)pyrazin-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; or its pharmaceutical acceptable salts or solvates. In some embodiments, the methods further comprise (after (b)) (c) determining whether the cancer cells in the sample obtained from the individual have the RET inhibitor resistance mutation V804M, G810S, or G810R; and (d) if The subject has cancer cells containing at least one RET inhibitor resistance mutation, and the subject is administered an agent selected from Examples 1-10, Examples 11-20, Examples 21-34 as monotherapy or in combination with another anticancer agent. A compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable salt or solvate thereof; or (e) if the individual has cancer cells that do not contain a RET inhibitor resistance mutation, An additional dose of the first RET inhibitor of step (b) is then administered to the individual.

As another example, provided herein are methods for treating RET-associated cancer in an individual in need of such treatment, the method comprising (a) detecting the RET gene, RET kinase, or either of them in a sample from the individual a disorder of expression or activity or level; and (b) administering to the individual a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) determining whether cancer cells in a sample obtained from the individual have at least one RET inhibitor resistance mutation; and (d) if the individual has Cancer cells with at least one RET inhibitor resistance mutation, the subject is then administered a second RET inhibitor as monotherapy or in combination with another anticancer agent, wherein the second RET inhibitor is selected from the group consisting of: 4-(6-(4-Benzylpiperazin-1-yl)pyridin-3-yl)-6-(2-(N-morpholinyl)ethoxy)pyrazolo[1,5-a ]pyridine-3-carbonitrile; 6-(2-hydroxyethoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazepine Heterobicyclo[3.1.1]hept-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; (R)-6-(2-hydroxypropoxy) -4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile; 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6- Diazabicyclo[3.1.1]hept-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-(2-methoxyethoxy) -4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine- 3-formonitrile; 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-(6-methoxynicotinyl)-3,6-diazabicyclo[ 3.1.1] Hept-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-(2-(dimethylamino)ethoxy)- 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]hept-3-yl)pyridin-3-yl) Pyrazolo[1,5-a]pyridine-3-carbonitrile; 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo [3.1.1] Hept-3-yl)pyridin-3-yl)-6-(2-(N-morpholinyl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile ;4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]hept-3-yl)pyridin-3-yl )-6-((1-methyl-1H-imidazol-4-yl)methoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile; and 6-ethoxy-4-( 5-(6-((5-fluoro-6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]hept-3-yl)pyrazine-2- base) pyrazolo[1,5-a]pyridine-3-carbonitrile; or a pharmaceutically acceptable salt or solvate thereof; or (e) if the individual has cancer that does not contain a RET inhibitor resistance cells, then administer an additional dose of the compound of formula I of step (b) or a pharmaceutically acceptable salt or solvate thereof to the individual. In some embodiments, provided herein are methods for treating a RET-associated cancer in an individual in need of such treatment, the method comprising (a) detecting the RET gene, RET kinase, or either of them in a sample from the individual and (b) administering a therapeutically effective amount of a compound of formula I selected from examples 1-10, examples 11-20, examples 21-34 or a pharmaceutically acceptable salt thereof or solvates. In some embodiments, the methods further comprise (after (b)) (c) determining whether cancer cells in a sample obtained from the individual have at least one RET inhibitor resistance mutation; and (d) if the individual has Cancer cells with at least one RET inhibitor resistance mutation, the subject is then administered a second RET inhibitor as monotherapy or in combination with another anticancer agent, wherein the second RET inhibitor is selected from the group consisting of: 4-(6-(4-Benzylpiperazin-1-yl)pyridin-3-yl)-6-(2-(N-morpholinyl)ethoxy)pyrazolo[1,5-a ]pyridine-3-carbonitrile; 6-(2-hydroxyethoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazepine Heterobicyclo[3.1.1]hept-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; (R)-6-(2-hydroxypropoxy) -4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile; 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6- Diazabicyclo[3.1.1]hept-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-(2-methoxyethoxy) -4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine- 3-formonitrile; 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-(6-methoxynicotinyl)-3,6-diazabicyclo[ 3.1.1] Hept-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-(2-(dimethylamino)ethoxy)- 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]hept-3-yl)pyridin-3-yl) Pyrazolo[1,5-a]pyridine-3-carbonitrile; 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo [3.1.1] Hept-3-yl)pyridin-3-yl)-6-(2-(N-morpholinyl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile ;4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]hept-3-yl)pyridin-3-yl )-6-((1-methyl-1H-imidazol-4-yl)methoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile; and 6-ethoxy-4-( 5-(6-((5-fluoro-6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]hept-3-yl)pyrazine-2- base) pyrazolo[1,5-a]pyridine-3-carbonitrile; or a pharmaceutically acceptable salt or solvate thereof; or (e) if the individual has cancer that does not contain a RET inhibitor resistance cells, then administer an additional dose of the compound of formula I of step (b) or a pharmaceutically acceptable salt or solvate thereof to the individual. In some embodiments, provided herein are methods for treating a RET-associated cancer in an individual in need of such treatment, the method comprising (a) detecting one or more fusion proteins of Table 1 in a sample from the individual and/or or one or more RET kinase protein point mutations/insertions/deletions of Table 2; and (b) administering a therapeutically effective amount of a compound of formula I selected from examples 1-10, examples 11-20, examples 21-34 or Its pharmaceutically acceptable salt or solvate. In some embodiments, the methods further comprise (after (b)) (c) determining whether the cancer cells in the sample obtained from the individual have at least one RET inhibitor resistance mutation of Table 3 or 4; and (d ) if the individual has cancer cells containing at least one RET inhibitor resistance mutation, administering to the individual a second RET inhibitor, either as monotherapy or in combination with another anticancer agent, wherein the second RET inhibitor is selected from The group consisting of: 4-(6-(4-benzylpiperazin-1-yl)pyridin-3-yl)-6-(2-(N-morpholinyl)ethoxy)pyrazolo[ 1,5-a]pyridine-3-carbonitrile; 6-(2-hydroxyethoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3 ,6-diazabicyclo[3.1.1]hept-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; (R)-6-(2- Hydroxypropoxy)-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5 -a]pyridine-3-carbonitrile; 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl) -3,6-diazabicyclo[3.1.1]hept-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-(2-methoxy Ethoxy)-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5 -a]pyridine-3-carbonitrile; 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-(6-methoxynicotinyl)-3,6- Diazabicyclo[3.1.1]hept-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-(2-(dimethylamino) Ethoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]hept-3-yl)pyridine -3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6 -Diazabicyclo[3.1.1]hept-3-yl)pyridin-3-yl)-6-(2-(N-morpholinyl)ethoxy)pyrazolo[1,5-a]pyridine -3-carbonitrile; 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]hept-3-yl) pyridin-3-yl)-6-((1-methyl-1H-imidazol-4-yl)methoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile; and 6-ethoxy Base-4-(5-(6-((5-fluoro-6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]hept-3-yl) Pyrazin-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; or a pharmaceutically acceptable salt or solvate thereof; or (e) if the individual has For cancer cells with resistance mutations, an additional dose of the compound of formula I in step (b) or a pharmaceutically acceptable salt or solvate thereof is administered to the individual. In some embodiments, provided herein are methods for treating RET-associated cancer in an individual in need of such treatment, the method comprising (a) detecting the fusion protein KIF5B-RET in a sample from the individual; and (b) A therapeutically effective amount of a compound of formula I selected from Examples 1-10, Examples 11-20, Examples 21-34, or a pharmaceutically acceptable salt or solvate thereof is administered to the individual. In some embodiments, the methods further comprise (after (b)) (c) determining whether the cancer cells in the sample obtained from the individual have the RET inhibitor resistance mutation V804M, G810S, or G810R; and (d) if The individual has cancer cells containing at least one RET inhibitor resistance mutation, the individual is administered a second RET inhibitor as monotherapy or in combination with another anticancer agent, wherein the second RET inhibitor is selected from the group consisting of Group: 4-(6-(4-benzylpiperazin-1-yl)pyridin-3-yl)-6-(2-(N-morpholinyl)ethoxy)pyrazolo[1, 5-a]pyridine-3-carbonitrile; 6-(2-hydroxyethoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6 -diazabicyclo[3.1.1]hept-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; (R)-6-(2-hydroxypropyl Oxy)-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a ]pyridine-3-carbonitrile; 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3 ,6-diazabicyclo[3.1.1]hept-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-(2-methoxyethyl Oxy)-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a ]pyridine-3-carbonitrile; 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-(6-methoxynicotinyl)-3,6-diazepine Heterobicyclo[3.1.1]hept-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-(2-(dimethylamino)ethoxy Base)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]hept-3-yl)pyridine-3 -yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-di Azabicyclo[3.1.1]hept-3-yl)pyridin-3-yl)-6-(2-(N-morpholinyl)ethoxy)pyrazolo[1,5-a]pyridine-3 -carbonitrile; 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]hept-3-yl)pyridine- 3-yl)-6-((1-methyl-1H-imidazol-4-yl)methoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile; and 6-ethoxy- 4-(5-(6-((5-fluoro-6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]hept-3-yl)pyrazine -2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; or a pharmaceutically acceptable salt or solvate thereof; or (e) if the individual has RET inhibitor-free resistance For mutated cancer cells, an additional dose of the compound of formula I of step (b) or a pharmaceutically acceptable salt or solvate thereof is administered to the individual.

In some embodiments, provided herein are methods for treating a RET-associated cancer in an individual in need of such treatment, the method comprising (a) detecting the RET gene, RET kinase, or either of them in a sample from the individual and (b) administering to the individual a therapeutically effective amount of a first RET inhibitor, wherein the first RET inhibitor is selected from the group consisting of: N-(1-(5-( 3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidine- 4-yl)benzamide; 6-ethoxy-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyridine Azolo[1,5-a]pyridine-3-carbonitrile; 6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-(pyridin-2-yloxy)nitro Heterobutan-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-(2-hydroxy-2-methylpropoxy)-4-( 6-(4-((6-methoxypyridazin-3-yl)oxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-methyl Nitrile; (S)-6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-(pyridin-2-yloxy)pyrrolidin-1-yl)pyridine-3- Base) pyrazolo[1,5-a]pyridine-3-carbonitrile; N-(1-(5-(3-cyano-6-((3-fluoro-1-methylazetidine- 3-yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-5-fluoro-2-methyl phenylbenzamide; 3-chloro-N-(1-(5-(3-cyano-6-((3-fluoro-1-methylazetidin-3-yl)methoxy)pyridine Azolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide; N-((3S,4S)-1-( 5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-hydroxypiperidin-4-yl)-3-methan 6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridine -3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; and 3-chloro-N-((3S,4S)-1-(5-(3-cyano-6-ethane Oxypyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-3-hydroxypiperidin-4-yl)pyridinecarboxamide; or a pharmaceutically acceptable salt thereof or solvates. In some embodiments, the methods further comprise (after (b)) (c) determining whether cancer cells in a sample obtained from the individual have at least one RET inhibitor resistance mutation; and (d) if the individual has For cancer cells with at least one RET inhibitor resistance mutation, a compound of formula I or a pharmaceutically acceptable salt or solvate thereof is administered to the individual as monotherapy or in combination with another anticancer agent; or (e ) if the individual has cancer cells that do not contain a RET inhibitor resistance mutation, then administering an additional dose of the first RET inhibitor of step (b) to the individual.

In some embodiments, provided herein are methods for treating a RET-associated cancer in an individual in need of such treatment, the method comprising (a) detecting the RET gene, RET kinase, or either of them in a sample from the individual and (b) administering to the individual a therapeutically effective amount of a first RET inhibitor, wherein the first RET inhibitor is selected from the group consisting of: N-(1-(5-( 3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidine- 4-yl)benzamide; 6-ethoxy-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyridine Azolo[1,5-a]pyridine-3-carbonitrile; 6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-(pyridin-2-yloxy)nitro Heterobutan-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-(2-hydroxy-2-methylpropoxy)-4-( 6-(4-((6-methoxypyridazin-3-yl)oxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-methyl Nitrile; (S)-6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-(pyridin-2-yloxy)pyrrolidin-1-yl)pyridine-3- Base) pyrazolo[1,5-a]pyridine-3-carbonitrile; N-(1-(5-(3-cyano-6-((3-fluoro-1-methylazetidine- 3-yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-5-fluoro-2-methyl phenylbenzamide; 3-chloro-N-(1-(5-(3-cyano-6-((3-fluoro-1-methylazetidin-3-yl)methoxy)pyridine Azolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide; N-((3S,4S)-1-( 5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-hydroxypiperidin-4-yl)-3-methan 6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridine -3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; and 3-chloro-N-((3S,4S)-1-(5-(3-cyano-6-ethane Oxypyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-3-hydroxypiperidin-4-yl)pyridinecarboxamide; or a pharmaceutically acceptable salt thereof or solvates. In some embodiments, the methods further comprise (after (b)) (c) determining whether cancer cells in a sample obtained from the individual have at least one RET inhibitor resistance mutation; and (d) if the individual has For cancer cells with at least one RET inhibitor resistance mutation, a compound of formula I selected from Examples 1-10, Examples 11-20, Examples 21-34 is administered to the individual as monotherapy or in combination with another anticancer agent or a pharmaceutically acceptable salt or solvate thereof; or (e) if the individual has cancer cells that do not contain a RET inhibitor resistance mutation, then administering to the individual an additional dose of the first RET of step (b) Inhibitor.

In some embodiments, provided herein is a method of treating a RET-associated cancer in an individual in need of such treatment, the method comprising (a) detecting in a sample from the individual one or more fusion proteins of Table 1 and/or a or more of the RET kinase protein point mutations/insertions/deletions of Table 2; and (b) administering to the individual a therapeutically effective amount of a first RET inhibitor, wherein the first RET inhibitor is selected from the group consisting of: N-( 1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4 -Methylpiperidin-4-yl)benzamide; 6-ethoxy-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridine -3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-(pyridine-2 -yloxy)azetidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-(2-hydroxy-2-methylpropoxy Base)-4-(6-(4-((6-methoxypyridazin-3-yl)oxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a ]pyridine-3-carbonitrile; (S)-6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-(pyridin-2-yloxy)pyrrolidine-1- Base) pyridin-3-yl) pyrazolo[1,5-a]pyridine-3-carbonitrile; N-(1-(5-(3-cyano-6-((3-fluoro-1-methyl Baseazetidin-3-yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-5 -Fluoro-2-methylbenzamide; 3-chloro-N-(1-(5-(3-cyano-6-((3-fluoro-1-methylazetidin-3-yl )methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)pyridinecarboxamide; N-((3S, 4S)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-hydroxypiperidine-4- base)-3-methylbutanamide; 6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidine -1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; and 3-chloro-N-((3S,4S)-1-(5-(3- Cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-3-hydroxypiperidin-4-yl)pyridinecarboxamide; or its medicine Pharmaceutically acceptable salts or solvates. In some embodiments, the methods further comprise (after (b)) (c) determining whether the cancer cells in the sample obtained from the individual have at least one RET inhibitor resistance mutation of Table 3 or 4; and (d ) if the subject has cancer cells containing at least one RET inhibitor resistance mutation, administering to the subject selected from Examples 1-10, Examples 11-20, Example 21- A compound of formula I of 34, or a pharmaceutically acceptable salt or solvate thereof; or (e) if the individual has cancer cells that do not contain a RET inhibitor resistance mutation, the step of administering an additional dose to the individual (b ) the first RET inhibitor.

In some embodiments, provided herein is a method of treating a RET-associated cancer in an individual in need of such treatment, the method comprising (a) detecting the fusion protein KIF5B-RET in a sample from the individual; and (b) administering to the individual administering a therapeutically effective amount of a first RET inhibitor, wherein the first RET inhibitor is selected from the group consisting of: N-(1-(5-(3-cyano-6-(2-hydroxy-2-methanol ylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)benzamide; 6-ethoxy- 4-(6-(4-Hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile ; 6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-(pyridin-2-yloxy)azetidin-1-yl)pyridin-3-yl)pyridine Azolo[1,5-a]pyridine-3-carbonitrile; 6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-((6-methoxypyridazine- 3-yl)oxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; (S)-6-(2-hydroxyl-2- Methylpropoxy)-4-(6-(3-(pyridin-2-yloxy)pyrrolidin-1-ylpyridin-3-yl)pyrazolo[1,5-a]pyridine-3- Carbonitrile; N-(1-(5-(3-cyano-6-((3-fluoro-1-methylazetidin-3-yl)methoxy)pyrazolo[1,5- a] pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-5-fluoro-2-methylbenzamide; 3-chloro-N-(1-( 5-(3-cyano-6-((3-fluoro-1-methylazetidin-3-yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridine -2-yl)-4-methylpiperidin-4-yl)pyridinamide; N-((3S,4S)-1-(5-(3-cyano-6-ethoxypyrazolo [1,5-a]pyridin-4-yl)pyridin-2-yl)-3-hydroxypiperidin-4-yl)-3-methylbutanamide; 6-(2-hydroxy-2-methyl Propoxy)-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine -3-carbonitrile; and 3-chloro-N-((3S,4S)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridine-4- or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) determining whether cancer cells in a sample obtained from the individual have the RET inhibitor resistance mutation V804M, G810S, or G810R; and (d) if the individual has at least one RET inhibitor resistance mutation For cancer cells, a compound of formula I selected from examples 1-10, examples 11-20, examples 21-34 or a pharmaceutically acceptable compound thereof is administered to the individual in the form of monotherapy or in combination with another anticancer agent. salt or solvate, or a pharmaceutically acceptable salt or solvate thereof; or (e) if the individual has cancer cells that do not contain a RET inhibitor resistance mutation, the step of administering an additional dose to the individual ( b) The first RET inhibitor.

As another example, provided herein are methods for treating RET-associated cancer in an individual in need of such treatment, the method comprising (a) detecting the RET gene, RET kinase, or either of them in a sample from the individual a disorder of expression or activity or level; and (b) administering to the individual a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) determining whether cancer cells in a sample obtained from the individual have at least one RET inhibitor resistance mutation; and (d) if the individual has Cancer cells with at least one RET inhibitor resistance mutation, the subject is then administered a second RET inhibitor as monotherapy or in combination with another anticancer agent, wherein the second RET inhibitor is selected from the group consisting of: N-(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl )-4-methylpiperidin-4-yl)benzamide; 6-ethoxy-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidine-1- yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-( Pyridin-2-yloxy)azetidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-(2-hydroxy-2-methyl Propyloxy)-4-(6-(4-((6-methoxypyridazin-3-yl)oxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1, 5-a] pyridine-3-carbonitrile; (S)-6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-(pyridin-2-yloxy)pyrrolidine -1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; N-(1-(5-(3-cyano-6-((3-fluoro- 1-methylazetidin-3-yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl )-5-fluoro-2-methylbenzamide; 3-chloro-N-(1-(5-(3-cyano-6-((3-fluoro-1-methylazetidine- 3-yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)pyridinamide; N-( (3S,4S)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-hydroxypiperidine -4-yl)-3-methylbutanamide; 6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl ) piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; and 3-chloro-N-((3S,4S)-1-(5- (3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-3-hydroxypiperidin-4-yl)pyridinecarboxamide; or a pharmaceutically acceptable salt or solvate thereof; or (e) if the individual has cancer cells that do not contain a RET inhibitor resistance mutation, then administering an additional dose of the compound of formula I of step (b) to the individual or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, provided herein are methods for treating a RET-associated cancer in an individual in need of such treatment, the method comprising (a) detecting the RET gene, RET kinase, or either of them in a sample from the individual and (b) administering a therapeutically effective amount of a compound of formula I selected from examples 1-10, examples 11-20, examples 21-34 or a pharmaceutically acceptable salt thereof or solvates. In some embodiments, the methods further comprise (after (b)) (c) determining whether cancer cells in a sample obtained from the individual have at least one RET inhibitor resistance mutation; and (d) if the individual has Cancer cells with at least one RET inhibitor resistance mutation, the subject is then administered a second RET inhibitor as monotherapy or in combination with another anticancer agent, wherein the second RET inhibitor is selected from the group consisting of: N-(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl )-4-methylpiperidin-4-yl)benzamide; 6-ethoxy-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidine-1- yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-( Pyridin-2-yloxy)azetidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-(2-hydroxy-2-methyl Propyloxy)-4-(6-(4-((6-methoxypyridazin-3-yl)oxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1, 5-a] pyridine-3-carbonitrile; (S)-6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-(pyridin-2-yloxy)pyrrolidine -1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; N-(1-(5-(3-cyano-6-((3-fluoro- 1-methylazetidin-3-yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl )-5-fluoro-2-methylbenzamide; 3-chloro-N-(1-(5-(3-cyano-6-((3-fluoro-1-methylazetidine- 3-yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)pyridinamide; N-( (3S,4S)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-hydroxypiperidine -4-yl)-3-methylbutanamide; 6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl ) piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; and 3-chloro-N-((3S,4S)-1-(5- (3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-3-hydroxypiperidin-4-yl)pyridinecarboxamide; or a pharmaceutically acceptable salt or solvate thereof; or (e) if the individual has cancer cells that do not contain a RET inhibitor resistance mutation, then administering an additional dose of the compound of formula I of step (b) to the individual or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, provided herein are methods for treating a RET-associated cancer in an individual in need of such treatment, the method comprising (a) detecting one or more fusion proteins of Table 1 in a sample from the individual and/or or one or more RET kinase protein point mutations/insertions/deletions of Table 2; and (b) administering a therapeutically effective amount of a compound of formula I selected from examples 1-10, examples 11-20, examples 21-34 or Its pharmaceutically acceptable salt or solvate. In some embodiments, the methods further comprise (after (b)) (c) determining whether the cancer cells in the sample obtained from the individual have at least one RET inhibitor resistance mutation of Table 3 or 4; and (d ) if the individual has cancer cells containing at least one RET inhibitor resistance mutation, administering to the individual a second RET inhibitor, either as monotherapy or in combination with another anticancer agent, wherein the second RET inhibitor is selected from The group consisting of: N-(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl) Pyridin-2-yl)-4-methylpiperidin-4-yl)benzamide; 6-ethoxy-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl) Piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-(2-hydroxy-2-methylpropoxy)-4-(6 -(3-(pyridin-2-yloxy)azetidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-(2- Hydroxy-2-methylpropoxy)-4-(6-(4-((6-methoxypyridazin-3-yl)oxy)piperidin-1-yl)pyridin-3-yl)pyridine Azolo[1,5-a]pyridine-3-carbonitrile; (S)-6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-(pyridin-2-yl Oxy)pyrrolidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; N-(1-(5-(3-cyano-6-( (3-fluoro-1-methylazetidin-3-yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiper Pyridin-4-yl)-5-fluoro-2-methylbenzamide; 3-chloro-N-(1-(5-(3-cyano-6-((3-fluoro-1-methyl Azetidin-3-yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinyl Amine; N-((3S,4S)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)- 3-hydroxypiperidin-4-yl)-3-methylbutanamide; 6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-hydroxy-4-(pyridine- 2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; and 3-chloro-N-((3S,4S)- 1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-3-hydroxypiperidin-4-yl) picolinamide; or a pharmaceutically acceptable salt or solvate thereof; or (e) if the individual has cancer cells that do not contain a RET inhibitor resistance mutation, the step of administering an additional dose to the individual (b ) compound of formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, provided herein is a method of treating a RET-associated cancer in an individual in need of such treatment, the method comprising (a) detecting the fusion protein KIF5B-RET in a sample from the individual; and (b) administering to the individual A therapeutically effective amount of a compound of formula I selected from Examples 1-10, Examples 11-20, Examples 21-34 or a pharmaceutically acceptable salt or solvate thereof is administered. In some embodiments, the methods further comprise (after (b)) (c) determining whether the cancer cells in the sample obtained from the individual have the RET inhibitor resistance mutation V804M, G810S, or G810R; and (d) if The individual has cancer cells containing at least one RET inhibitor resistance mutation, the individual is administered a second RET inhibitor as monotherapy or in combination with another anticancer agent, wherein the second RET inhibitor is selected from the group consisting of Group: N-(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridine- 2-yl)-4-methylpiperidin-4-yl)benzamide; 6-ethoxy-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidine -1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-(2-hydroxy-2-methylpropoxy)-4-(6-( 3-(pyridin-2-yloxy)azetidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-(2-hydroxy- 2-methylpropoxy)-4-(6-(4-((6-methoxypyridazin-3-yl)oxy)piperidin-1-yl)pyridin-3-yl)pyrazolo [1,5-a]pyridine-3-carbonitrile; (S)-6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-(pyridin-2-yloxy ) pyrrolidin-1-yl) pyridin-3-yl) pyrazolo[1,5-a]pyridine-3-carbonitrile; N-(1-(5-(3-cyano-6-((3 -Fluoro-1-methylazetidin-3-yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidine- 4-yl)-5-fluoro-2-methylbenzamide; 3-chloro-N-(1-(5-(3-cyano-6-((3-fluoro-1-methylazepine Cyclobut-3-yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)pyridinecarboxamide; N-((3S,4S)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3- Hydroxypiperidin-4-yl)-3-methylbutanamide; 6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-hydroxy-4-(pyridine-2- ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; and 3-chloro-N-((3S,4S)-1- (5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-3-hydroxypiperidin-4-yl)picolin amide; or a pharmaceutically acceptable salt or solvate thereof; or (e) if the individual has cancer cells that do not contain a RET inhibitor resistance mutation, then administering to the individual an additional dose of step (b) A compound of formula I or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments provided herein, circulating tumor DNA can be used to monitor a patient's response to a particular therapy, such as a first RET inhibitor, a second RET inhibitor, or a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof. matter) reaction. For example, prior to initiating treatment with a therapy as described herein (e.g., a first RET inhibitor, a second RET inhibitor, or a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof) , a biological sample can be obtained from an individual and the amount of circulating tumor DNA in the biological sample can be determined. This sample can be considered a baseline sample. The individual may then be administered one or more doses of a therapy as described herein (e.g., a first RET inhibitor, a second RET inhibitor, or a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof substance) and the level of circulating tumor DNA can be monitored (eg, after the first dose, second dose, third dose, etc. or after one week, two weeks, three weeks, four weeks, etc.). If the amount of circulating tumor DNA is lower than the baseline sample (eg, 1% to about 99% reduction, 1% to about 95% reduction, 1% to about 90% reduction, 1% to about 85% reduction, 1% to about 80% reduction Reduced, 1% to approximately 75% reduced, 1% reduced to approximately 70% reduced, 1% reduced to approximately 65% reduced, 1% reduced to approximately 60% reduced, 1% reduced to approximately 55% reduced, 1% reduced to approximately 55% reduced, 1% reduced to approximately 65% reduced About 50% reduction, 1% reduction to about 45% reduction, 1% reduction to about 40% reduction, 1% reduction to about 35% reduction, 1% reduction to about 30% reduction, 1% reduction to about 25% reduction, 1% reduction to about 20% reduction, 1% reduction to about 15% reduction, 1% reduction to about 10% reduction, 1% to about 5% reduction, about 5% to about 99% reduction, about 10% to about 99% reduction % reduction, about 15% to about 99% reduction, about 20% to about 99% reduction, about 25% to about 99% reduction, about 30% to about 99% reduction, about 35% to about 99% reduction, about 40% % to about 99% reduction, about 45% to about 99% reduction, about 50% to about 99% reduction, about 55% to about 99% reduction, about 60% to about 99% reduction, about 65% to about 99% reduction Reduced, about 70% to about 99% reduced, about 75% to about 95% reduced, about 80% to about 99% reduced, about 90% to about 99% reduced, about 95% to about 99% reduced, about 5 % to about 10% reduction, about 5% to about 25% reduction, about 10% to about 30% reduction, about 20% to about 40% reduction, about 25% to about 50% reduction, about 35% to about 55% reduction reduction, about 40% to about 60% reduction, about 50% reduction to about 75% reduction, about 60% reduction to about 80% reduction, or about 65% to about 85% reduction, etc.), this is indicative of a response to therapy. In some embodiments, the level of circulating tumor DNA is reduced such that it is below the detection limit of the instrument. In some embodiments, the amount of circulating tumor DNA in a biological sample (n) obtained from a patient is compared to a previously taken sample (n-1). If the level of circulating tumor DNA in the nth sample is lower than that of the n-1th sample (for example, 1% to about 99% reduction, 1% to about 95% reduction, 1% to about 90% reduction, 1% to about 85% reduction, 1% to about 80% reduction, 1% to about 75% reduction, 1% reduction to about 70% reduction, 1% reduction to about 65% reduction, 1% reduction to about 60% reduction, 1% reduction to about 55% reduction, 1% reduction to about 50% reduction, 1% reduction to about 45% reduction, 1% reduction to about 40% reduction, 1% reduction to about 35% reduction, 1% reduction to about 30% reduction , 1% reduction to approximately 25% reduction, 1% reduction to approximately 20% reduction, 1% reduction to approximately 15% reduction, 1% reduction to approximately 10% reduction, 1% to approximately 5% reduction, approximately 5% to approximately 5% reduction 99% reduction, about 10% to about 99% reduction, about 15% to about 99% reduction, about 20% to about 99% reduction, about 25% to about 99% reduction, about 30% to about 99% reduction, about 35% to about 99% reduction, about 40% to about 99% reduction, about 45% to about 99% reduction, about 50% to about 99% reduction, about 55% to about 99% reduction, about 60% to about 99% reduction % reduction, about 65% to about 99% reduction, about 70% to about 99% reduction, about 75% to about 95% reduction, about 80% to about 99% reduction, about 90% to about 99% reduction, about 95% to about 99% reduction, about 5% to about 10% reduction, about 5% to about 25% reduction, about 10% to about 30% reduction, about 20% to about 40% reduction, about 25% to about 50% reduction % reduction, about 35% to about 55% reduction, about 40% to about 60% reduction, about 50% reduction to about 75% reduction, about 60% reduction to about 80% reduction, or about 65% to about 85% reduction etc.), then this indication is responsive to therapy. In some embodiments, the level of circulating tumor DNA is reduced such that it is below the detection limit of the instrument. In the event of a response to therapy, one or more doses of therapy can be administered to the individual and monitoring of circulating tumor DNA can continue.

If the amount of circulating tumor DNA in the sample is higher than baseline (eg, 1% to about 99% increase, 1% to about 95% increase, 1% to about 90% increase, 1% to about 85% increase, 1% to about 80% increase, 1% to about 75% increase, 1% increase to about 70% increase, 1% increase to about 65% increase, 1% increase to about 60% increase, 1% increase to about 55% increase, 1% increase Increase to approximately 50% increase, 1% increase to approximately 45% increase, 1% increase to approximately 40% increase, 1% increase to approximately 35% increase, 1% increase to approximately 30% increase, 1% increase to approximately 25% increase Increase, 1% increase to about 20% increase, 1% increase to about 15% increase, 1% increase to about 10% increase, 1% to about 5% increase, about 5% to about 99% increase, about 10% to about 10% increase about 99% increase, about 15% to about 99% increase, about 20% to about 99% increase, about 25% to about 99% increase, about 30% to about 99% increase, about 35% to about 99% increase, About 40% to about 99% increase, about 45% to about 99% increase, about 50% to about 99% increase, about 55% to about 99% increase, about 60% to about 99% increase, about 65% to about 99% increase, about 65% to about 99% increase 99% increase, about 70% to about 99% increase, about 75% to about 95% increase, about 80% to about 99% increase, about 90% to about 99% increase, about 95% to about 99% increase, About 5% to about 10% increase, about 5% to about 25% increase, about 10% to about 30% increase, about 20% to about 40% increase, about 25% to about 50% increase, about 35% to about 30% increase 55% increase, about 40% to about 60% increase, about 50% increase to about 75% increase, about 60% increase to about 80% increase, or about 65% to about 85% increase, etc.), which may be indicative of a response to therapy resistance. If the circulating tumor DNA content in the nth sample is higher than that in the n-1th sample (for example, 1% to about 99% increase, 1% to about 95% increase, 1% to about 90% increase, 1% to about 90% increase, 1% to about 85% increase, 1% to about 80% increase, 1% to about 75% increase, 1% increase to about 70% increase, 1% increase to about 65% increase, 1% increase to about 60% increase, 1% increase to about 55% increase, 1% increase to about 50% increase, 1% increase to about 45% increase, 1% increase to about 40% increase, 1% increase to about 35% increase, 1% increase to about 30% increase , 1% to about 25% increase, 1% to about 20% increase, 1% to about 15% increase, 1% to about 10% increase, 1% to about 5% increase, about 5% to about 5% increase 99% increase, about 10% to about 99% increase, about 15% to about 99% increase, about 20% to about 99% increase, about 25% to about 99% increase, about 30% to about 99% increase, about 30% to about 99% increase, about 35% to about 99% increase, about 40% to about 99% increase, about 45% to about 99% increase, about 50% to about 99% increase, about 55% to about 99% increase, about 60% to about 99% increase % increase, about 65% to about 99% increase, about 70% to about 99% increase, about 75% to about 95% increase, about 80% to about 99% increase, about 90% to about 99% increase, about 95% to about 99% increase, about 5% to about 10% increase, about 5% to about 25% increase, about 10% to about 30% increase, about 20% to about 40% increase, about 25% to about 50% increase % increase, about 35% to about 55% increase, about 40% to about 60% increase, about 50% increase to about 75% increase, about 60% increase to about 80% increase, or about 65% to about 85% increase, etc. ), this may indicate resistance to therapy. When resistance to therapy is suspected, an individual may undergo one or more of imaging, biopsy, surgery, or other diagnostic tests. In some embodiments, when resistance to therapy is suspected, a compound capable of treating RET inhibitor resistance (such as a compound of formula I provided herein) may be administered (as monotherapy or in combination with the aforementioned therapies) to the individual or a pharmaceutically acceptable salt or solvate thereof). See, eg, Cancer Discov; 7(12); 1368-70 (2017); and Cancer Discov; 7(12); 1394-403 (2017).

In some embodiments provided herein, protein biomarkers can be used to monitor a patient's response to a particular therapy, such as a first RET inhibitor, a second RET inhibitor, or a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof. matter) reaction. For example, prior to initiating treatment with a therapy as described herein (e.g., a first RET inhibitor, a second RET inhibitor, or a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof) , a biological sample can be obtained from an individual and the amount of a protein biomarker in the biological sample can be determined. This sample can be considered a baseline sample. The individual may then be administered one or more doses of a therapy as described herein (e.g., a first RET inhibitor, a second RET inhibitor, or a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof substance) and the levels of protein biomarkers can be monitored (eg, after the first dose, second dose, third dose, etc. or after one week, two weeks, three weeks, four weeks, etc.). If the level of the protein biomarker is lower than the baseline sample (eg, 1% to about 99% reduction, 1% to about 95% reduction, 1% to about 90% reduction, 1% to about 85% reduction, 1% to about 80% reduction Reduced, 1% to approximately 75% reduced, 1% reduced to approximately 70% reduced, 1% reduced to approximately 65% reduced, 1% reduced to approximately 60% reduced, 1% reduced to approximately 55% reduced, 1% reduced to approximately 55% reduced, 1% reduced to approximately 65% reduced About 50% reduction, 1% reduction to about 45% reduction, 1% reduction to about 40% reduction, 1% reduction to about 35% reduction, 1% reduction to about 30% reduction, 1% reduction to about 25% reduction, 1% reduction to about 20% reduction, 1% reduction to about 15% reduction, 1% reduction to about 10% reduction, 1% to about 5% reduction, about 5% to about 99% reduction, about 10% to about 99% reduction % reduction, about 15% to about 99% reduction, about 20% to about 99% reduction, about 25% to about 99% reduction, about 30% to about 99% reduction, about 35% to about 99% reduction, about 40% % to about 99% reduction, about 45% to about 99% reduction, about 50% to about 99% reduction, about 55% to about 99% reduction, about 60% to about 99% reduction, about 65% to about 99% reduction Reduced, about 70% to about 99% reduced, about 75% to about 95% reduced, about 80% to about 99% reduced, about 90% to about 99% reduced, about 95% to about 99% reduced, about 5 % to about 10% reduction, about 5% to about 25% reduction, about 10% to about 30% reduction, about 20% to about 40% reduction, about 25% to about 50% reduction, about 35% to about 55% reduction reduction, about 40% to about 60% reduction, about 50% reduction to about 75% reduction, about 60% reduction to about 80% reduction, or about 65% to about 85% reduction, etc.), this is indicative of a response to therapy. In some embodiments, the level of the protein biomarker is reduced such that it is below the detection limit of the instrument. In some embodiments, the amount of protein biomarkers in a biological sample (n) obtained from a patient is compared to a previously taken sample (n-1). If the protein biomarker content in the nth sample is lower than that in the n-1th sample (e.g., 1% to about 99% reduction, 1% to about 95% reduction, 1% to about 90% reduction, 1% to about 90% reduction, 1% to about 85% reduction, 1% to about 80% reduction, 1% to about 75% reduction, 1% reduction to about 70% reduction, 1% reduction to about 65% reduction, 1% reduction to about 60% reduction, 1% reduction to about 55% reduction, 1% reduction to about 50% reduction, 1% reduction to about 45% reduction, 1% reduction to about 40% reduction, 1% reduction to about 35% reduction, 1% reduction to about 30% reduction , 1% reduction to approximately 25% reduction, 1% reduction to approximately 20% reduction, 1% reduction to approximately 15% reduction, 1% reduction to approximately 10% reduction, 1% to approximately 5% reduction, approximately 5% to approximately 5% reduction 99% reduction, about 10% to about 99% reduction, about 15% to about 99% reduction, about 20% to about 99% reduction, about 25% to about 99% reduction, about 30% to about 99% reduction, about 35% to about 99% reduction, about 40% to about 99% reduction, about 45% to about 99% reduction, about 50% to about 99% reduction, about 55% to about 99% reduction, about 60% to about 99% reduction % reduction, about 65% to about 99% reduction, about 70% to about 99% reduction, about 75% to about 95% reduction, about 80% to about 99% reduction, about 90% to about 99% reduction, about 95% to about 99% reduction, about 5% to about 10% reduction, about 5% to about 25% reduction, about 10% to about 30% reduction, about 20% to about 40% reduction, about 25% to about 50% reduction % reduction, about 35% to about 55% reduction, about 40% to about 60% reduction, about 50% reduction to about 75% reduction, about 60% reduction to about 80% reduction, or about 65% to about 85% reduction etc.), then this indication is responsive to therapy. In some embodiments, the level of the protein biomarker is reduced such that it is below the detection limit of the instrument. In the event of a response to therapy, one or more doses of therapy can be administered to the individual and protein biomarkers can continue to be monitored.

If the amount of protein biomarker in the sample is higher than baseline (e.g., 1% to about 99% increase, 1% to about 95% increase, 1% to about 90% increase, 1% to about 85% increase, 1% to about 85% increase, 1% to About 80% increase, 1% to about 75% increase, 1% increase to about 70% increase, 1% increase to about 65% increase, 1% increase to about 60% increase, 1% increase to about 55% increase, 1 % increase to approximately 50% increase, 1% increase to approximately 45% increase, 1% increase to approximately 40% increase, 1% increase to approximately 35% increase, 1% increase to approximately 30% increase, 1% increase to approximately 25% increase % increase, 1% increase to approximately 20% increase, 1% increase to approximately 15% increase, 1% increase to approximately 10% increase, 1% to approximately 5% increase, approximately 5% to approximately 99% increase, approximately 10% increase to about 99% increase, about 15% to about 99% increase, about 20% to about 99% increase, about 25% to about 99% increase, about 30% to about 99% increase, about 35% to about 99% increase , about 40% to about 99% increase, about 45% to about 99% increase, about 50% to about 99% increase, about 55% to about 99% increase, about 60% to about 99% increase, about 65% to about 99% increase, about 65% to about 99% increase About 99% increase, about 70% to about 99% increase, about 75% to about 95% increase, about 80% to about 99% increase, about 90% to about 99% increase, about 95% to about 99% increase , about 5% to about 10% increase, about 5% to about 25% increase, about 10% to about 30% increase, about 20% to about 40% increase, about 25% to about 50% increase, about 35% to about 35% increase about 55% increase, about 40% to about 60% increase, about 50% increase to about 75% increase, about 60% increase to about 80% increase, or about 65% to about 85% increase, etc.), then this may indicate Resistance to therapy. If the protein biomarker content in the nth sample is higher than that in the n-1th sample (e.g., 1% to about 99% increase, 1% to about 95% increase, 1% to about 90% increase, 1% to about 90% increase, 1% to About 85% increase, 1% to about 80% increase, 1% to about 75% increase, 1% increase to about 70% increase, 1% increase to about 65% increase, 1% increase to about 60% increase, 1% increase Increase to approximately 55% increase, 1% increase to approximately 50% increase, 1% increase to approximately 45% increase, 1% increase to approximately 40% increase, 1% increase to approximately 35% increase, 1% increase to approximately 30% increase Increase, 1% increase to about 25% increase, 1% increase to about 20% increase, 1% increase to about 15% increase, 1% increase to about 10% increase, 1% to about 5% increase, about 5% to about 99% increase, about 10% to about 99% increase, about 15% to about 99% increase, about 20% to about 99% increase, about 25% to about 99% increase, about 30% to about 99% increase, About 35% to about 99% increase, about 40% to about 99% increase, about 45% to about 99% increase, about 50% to about 99% increase, about 55% to about 99% increase, about 60% to about 99% increase, about 60% to about 99% increase 99% increase, about 65% to about 99% increase, about 70% to about 99% increase, about 75% to about 95% increase, about 80% to about 99% increase, about 90% to about 99% increase, About 95% to about 99% increase, about 5% to about 10% increase, about 5% to about 25% increase, about 10% to about 30% increase, about 20% to about 40% increase, about 25% to about 25% increase 50% increase, about 35% to about 55% increase, about 40% to about 60% increase, about 50% increase to about 75% increase, about 60% increase to about 80% increase, or about 65% to about 85% increase increase, etc.), this may indicate resistance to therapy. When resistance to therapy is suspected, an individual may undergo one or more of imaging, biopsy, surgery, or other diagnostic tests. In some embodiments, when resistance to therapy is suspected, a compound capable of treating RET inhibitor resistance (such as a compound of formula I provided herein or a pharmaceutically acceptable salt or solvate thereof).

In some embodiments, one or more protein biomarkers are monitored. The particular protein biomarkers to monitor can depend on the type of cancer and can be readily identified by those of ordinary skill in the art. Non-limiting examples of protein biomarkers include: CA 125, carcinoembryonic antigen (CEA), calcitonin, thyroglobulin, adrenocorticotropic hormone (ACTH), cortisol, CA 19-9, prolactin, hepatocyte Growth factor, osteopontin, myeloperoxidase, tissue inhibitor of metalloproteinase 1, angiopoietin-1 (Ang-1), cytokeratin 19 (CK-19), tissue inhibitor of metalloproteinase-1 (TIMP- 1), Chitinase 3 (such as Chitinase-1 (YKL-40)), Galectin-3 (GAL-3), CYFRA 21-1 (Cytokeratin), EPCAM (Epithelial Cell Adhesion Molecule) , ProGRP (Gastrin-releasing Peptide) and CEACAM (Carcinoembryonic Antigen). See eg Cohen JD, Li L, Wang Y et al., Detection and localization of surgically resectable cancers with a multi-analyte blood test. Science ; published online Jan 18, 2018. pii: eaar3247. DOI: 10.1126/science.aar3247 ; Fawaz M Makki et al. Serum biomarkers of papillary thyroid cancer. J Otolaryngol Head Neck Surg. 2013; 42(1): 16; and Tatiana N. Zamay et al. Current and Prospective Protein Biomarkers of Lung Cancer. Cancers (Basel). 2017 Nov; 9(11): 155. In some embodiments, the biomarkers include one or more of CEA, calcitonin, thyroglobulin, ACTH, and cortisol. In some embodiments, the cancer is medullary thyroid cancer and the protein biomarkers include CEA and calcitonin. In some embodiments, the cancer is nonmedullary thyroid cancer and the protein biomarker comprises thyroglobulin. In some embodiments, the biomarkers are ACTH and Cortisol (eg, when the patient has Cushing's disease associated with their cancer).

Also provided herein are methods for treating a RET-associated cancer in an individual comprising (a) presenting to an individual identified or diagnosed as having a RET-associated cancer, such as any of the types of RET-associated cancers described herein ( One or more (e.g., two or more, three or more multiple, four or more, five or more, or ten or more) doses of the first RET kinase inhibitor; (b) after step (a), assaying a biological sample obtained from the individual (e.g., the amount of circulating tumor DNA in a biological sample comprising blood, serum, or plasma); (c) as monotherapy or in combination with another anti-cancer agent, to be identified as having a reference amount of circulating tumor DNA (e.g. A therapeutically effective amount of a second RET inhibitor or a compound of Formula I or a pharmaceutical thereof administered to an individual having approximately the same or elevated circulating tumor DNA levels compared to any of the reference levels of circulating tumor DNA described herein) acceptable salts or solvates. In some examples of these methods, the reference level of circulating tumor DNA is the level of circulating tumor DNA in a biological sample obtained from the individual prior to step (a). Some embodiments of these methods further comprise determining the amount of circulating tumor DNA in the biological sample obtained from the individual prior to step (a). In some examples of these methods, the reference level of circulating tumor DNA is a threshold level of circulating tumor DNA (e.g., the average level of circulating tumor DNA in a population of individuals with similar RET-associated cancers with similar RET-associated cancer stage, but received ineffective therapy or placebo, or had not received therapeutic treatment; or the amount of circulating tumor DNA in an individual with a similar RET-associated cancer with a similar RET-associated cancer stage, but received ineffective therapy or placebo, or has not received therapeutic treatment). In some examples of these methods, the first RET inhibitor is selected from the group consisting of cabozantinib, vandetanib, alectinib, apatinib, sitravatinib , sorafenib, lenvatinib, ponatinib, dovitinib, sunitinib, fretinib, LOXO-292, BLU667 and BLU6864.

Also provided herein are methods for treating RET-associated cancer in an individual comprising administering to an individual a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof: (i) identified or diagnosed as having Have a RET-associated cancer (e.g., any of the types of RET-associated cancers described herein) (e.g., identified or diagnosed using any of the exemplary methods described herein or known in the art) RET-associated cancers), (ii) have previously administered one or more (e.g., two or more, three or more, four or more, five or more, or ten or more multiple) doses of the second RET kinase inhibitor, and (iii) following previous administration of one or more doses of the second RET kinase inhibitor, identified as having a reference level of circulating tumor DNA (such as described herein or any of the reference levels of circulating tumor DNA known in the art) compared to approximately the same or increased circulating tumor DNA levels. In some embodiments of these methods, the reference level of circulating tumor DNA is a biological sample (e.g., a biological sample comprising blood, plasma, or serum) obtained from an individual prior to administration of one or more doses of the second RET kinase inhibitor. ) in circulating tumor DNA content. Some embodiments of these methods further comprise determining the amount of circulating tumor DNA in a biological sample obtained from the individual prior to administering the one or more doses of the second RET kinase inhibitor. In some examples of these methods, the reference level of circulating tumor DNA is a threshold level of circulating tumor DNA (e.g., the average level of circulating tumor DNA in a population of individuals with similar RET-associated cancers with similar RET-associated cancer stage, but received ineffective therapy or placebo, or had not received therapeutic treatment; or the amount of circulating tumor DNA in an individual with a similar RET-associated cancer with a similar RET-associated cancer stage, but received ineffective therapy or placebo, or has not received therapeutic treatment). In some embodiments of these methods, the second RET kinase inhibitor can be selected from the group consisting of cabozantinib, vandetanib, alectinib, apatinib, stretinib, Rafenib, lenvatinib, ponatinib, dovitinib, sunitinib, fretinib, LOXO-292 , BLU667 and BLU6864.

Also provided herein are methods for treating a RET-associated cancer in an individual comprising: (a) as a monotherapy to any of the types of RET-associated cancers identified or diagnosed as having a RET-associated cancer described herein (e.g., an individual identified or diagnosed with a RET-associated cancer using any of the methods described herein or known in the art) administered one or more doses of a compound of formula I or a pharmaceutical thereof A pharmaceutically acceptable salt or solvate; (b) after step (a), determining the amount of circulating tumor DNA in a biological sample (such as a biological sample comprising blood, serum or plasma) obtained from the individual; (c ) to a circulating tumor identified as having about the same or an increase compared to a reference level of circulating tumor DNA, such as any of the exemplary reference levels of circulating tumor DNA described herein or known in the art Individuals with DNA content are administered a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, and other therapeutic agents or treatments (such as those described herein or for RET-associated cancers known in the art). any of the other therapeutic agents or treatments). In some embodiments of these methods, the additional therapeutic agent is a second RET kinase inhibitor (e.g., a RET kinase inhibitor selected from the group consisting of cabozantinib, vandetanib, alectinib, arpa tinib, stretinib, sorafenib, lenvatinib, ponatinib, dovitinib, sunitinib, fretinib, LOXO-292, BLU667 and BLU6864. In these methods In some instances of any of these, the additional therapeutic agent or treatment comprises one or more of: radiation therapy, chemotherapeutic agents (such as among the exemplary chemotherapeutic agents described herein or known in the art) any of the following), checkpoint inhibitors (such as any of the exemplary checkpoint inhibitors described herein or known in the art), surgery (such as at least partial tumor resection), and one or more other A kinase inhibitor (such as any of the exemplary kinase inhibitors described herein or known in the art). In some examples of these methods, the reference level of circulating tumor DNA is The amount of circulating tumor DNA in a biological sample previously obtained from the individual, such as a biological sample comprising blood, serum, or plasma. In some examples of these methods, the reference amount of circulating tumor DNA is a threshold amount of circulating tumor DNA (e.g. the average amount of circulating tumor DNA in a population of individuals with similar RET-associated cancers with a similar RET-associated cancer stage, but receiving ineffective therapy or placebo, or who have not received therapeutic treatment; or individuals The amount of circulating tumor DNA in an individual with a similar RET-associated cancer and with a similar RET-associated cancer stage but receiving ineffective therapy or a placebo, or who has not received therapeutic treatment).

Also provided herein are methods for treating RET-associated cancer in an individual comprising: administering to an individual a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, and other therapeutic agent or treatment: (i) identified or diagnosed as having a RET-associated cancer (e.g., any of the types of RET-associated cancers described herein) (e.g., using methods described herein or known in the art as having Individuals with RET-associated cancer), (ii) have previously administered one or more doses of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, as monotherapy, and (iii) have previously administered as monotherapy Administration of one or more (e.g. two or more, three or more, four or more, five or more or ten or more) doses of a compound of formula I or its A pharmaceutically acceptable salt or solvate is then identified as having a concentration about the same as or increased compared to a reference level of circulating tumor DNA, such as any of the exemplary reference levels of circulating tumor DNA described herein. High circulating tumor DNA content. In some embodiments of these methods, the reference level of circulating tumor DNA is administered as monotherapy with one or more (e.g., two or more, three or more, four or more , five or more or ten or more) doses of the compound of formula I or a pharmaceutically acceptable salt or solvate thereof, the content of circulating tumor DNA in a biological sample obtained from an individual. Some embodiments of these methods further comprise determining circulating tumor in a biological sample obtained from an individual prior to administering one or more doses of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, as monotherapy DNA content. In some examples of these methods, the reference level of circulating tumor DNA is a threshold level of circulating tumor DNA (e.g., the average level of circulating tumor DNA in a population of individuals with similar RET-associated cancers with similar RET-associated cancer stage, but received ineffective therapy or placebo, or had not received therapeutic treatment; or the amount of circulating tumor DNA in an individual with a similar RET-associated cancer with a similar RET-associated cancer stage, but received ineffective therapy or placebo, or has not received therapeutic treatment). In some embodiments of this method, the additional therapeutic agent is a second RET kinase inhibitor (e.g., a second RET kinase inhibitor selected from the group consisting of cabozantinib, vandetanib, alectinib, alectinib, Patinib, Stetinib, Sorafenib, Lenvatinib, Ponatinib, Dovitinib, Sunitinib, Fretinib, LOXO-292, BLU667 and BLU6864. In some embodiments of the methods, the additional therapeutic agent or treatment comprises one or more of: radiation therapy, a chemotherapeutic agent (such as any of the exemplary chemotherapeutic agents described herein or known in the art) , a checkpoint inhibitor (such as any of the exemplary checkpoint inhibitors described herein or known in the art), surgery (such as at least partial resection of a tumor), and one or more other kinase inhibitors (such as any of the kinase inhibitors described herein or known in the art).

Also provided herein is a method of selecting a treatment for an individual comprising: selecting a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, for an individual who: (i) is identified or diagnosed as having RET Associated cancer (e.g., any of the RET-associated cancers described herein) (e.g., an individual identified or diagnosed with a RET-associated cancer using any of the methods described herein or known in the art) , (ii) has previously administered one or more (e.g., two or more, three or more, four or more, five or more, or ten or more) doses A second RET kinase inhibitor (such as any of the RET kinase inhibitors described herein or known in the art), and (iii) upon administration of one or more doses of the second RET kinase inhibitor Following the dose, it is identified as having a circulating tumor DNA level that is about the same or increased compared to a reference level of circulating tumor DNA. In some embodiments of any of these methods, the reference level of circulating tumor DNA is a biological sample (e.g., comprising blood, serum, or plasma biological samples) in the circulating tumor DNA content. Some embodiments of these methods further comprise determining the amount of circulating tumor DNA in a biological sample obtained from the individual prior to administering the one or more doses of the second RET kinase inhibitor. In some examples of these methods, the reference level of circulating tumor DNA is a threshold level of circulating tumor DNA (e.g., the average level of circulating tumor DNA in a population of individuals with similar RET-associated cancers with similar RET-associated cancer stage, but received ineffective therapy or placebo, or had not received therapeutic treatment; or the amount of circulating tumor DNA in an individual with a similar RET-associated cancer with a similar RET-associated cancer stage, but received ineffective therapy or placebo, or has not received therapeutic treatment). In some embodiments of any of these methods, the second RET kinase inhibitor is selected from the group consisting of cabozantinib, vandetanib, alectinib, apatinib, stretinib, soratinib Fini, lenvatinib, ponatinib, dovitinib, sunitinib, fretinib, LOXO-292, BLU667 and BLU6864.

Also provided herein are methods of selecting a treatment for an individual comprising selecting a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, and other therapeutic agent or treatment for an individual who: (i) identifies or diagnosed with a RET-associated cancer (e.g., any of the RET-associated cancers described herein or known in the art) (e.g., using any of the methods described herein or known in the art identified or diagnosed as having a RET-associated cancer), (ii) have previously been administered one or more (e.g., two or more, three or more, four or more) as monotherapy , five or more or ten or more) doses of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, and (iii) administering one or more doses of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, is identified as having a circulating tumor DNA level that is about the same or increased compared to a reference level of circulating tumor DNA. In some embodiments of these methods, the reference level of circulating tumor DNA is obtained from an individual prior to administering one or more doses of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, as monotherapy The content of circulating tumor DNA in a biological sample (such as a biological sample including blood, serum or plasma). Some embodiments further comprise determining the level of circulating tumor DNA in a biological sample obtained from an individual prior to administering one or more doses of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, as monotherapy. In some examples of these methods, the reference level of circulating tumor DNA is a threshold level of circulating tumor DNA (e.g., the average level of circulating tumor DNA in a population of individuals with similar RET-associated cancers with similar RET-associated cancer stage, but received ineffective therapy or placebo, or had not received therapeutic treatment; or the amount of circulating tumor DNA in an individual with a similar RET-associated cancer with a similar RET-associated cancer stage, but received ineffective therapy or placebo, or has not received therapeutic treatment). In some embodiments of any of these methods, the additional therapeutic agent is a second RET kinase inhibitor (e.g., a second RET kinase inhibitor selected from the group consisting of cabozantinib, vandetanib, Alectinib, Apatinib, Stetinib, Sorafenib, Lenvatinib, Ponatinib, Dovitinib, Sunitinib, Fretinib, LOXO-292, BLU667 and BLU6864. In some embodiments of any of the methods described herein, the additional therapeutic agent or treatment includes one or more of: radiation therapy, chemotherapy agents (such as described herein or this any of the examples of chemotherapeutic agents known in the art), checkpoint inhibitors (such as any of the checkpoint inhibitors described herein or known in the art), surgery (such as at least partial resection of the tumor) and one or more other kinase inhibitors (such as any of those described herein or known in the art).

Also provided herein are methods for determining the efficacy of a treatment in an individual comprising: (a) assaying a biological sample (including, for example, blood, serum, or plasma) obtained at a first time point from an individual identified or diagnosed as having a RET-associated cancer (b) after the first time point and before the second time point, administer a treatment to the individual comprising one or more doses of a compound of formula I or its pharmaceutical (c) determining the amount of a second circulating tumor DNA in a biological sample (such as a biological sample comprising blood, serum or plasma) obtained from an individual at a second time point; and (d) Identifying that the treatment is effective in an individual determined to have a second circulating tumor DNA level that is reduced compared to a first circulating tumor DNA level; Not effective in individuals with high second circulating tumor DNA content. In some embodiments of these methods, the first time point is separated from the second time point by about 1 week to about 1 year (e.g., about 1 week to about 10 months, about 1 week to about 8 months, about 1 week to about 6 months months, about 1 week to about 4 months, about 1 week to about 3 months, about 1 week to about 2 months, about 1 week to about 1 month, or about 1 week to about 2 weeks).

Also provided herein are methods for determining whether an individual has developed resistance to the treatment comprising: (a) assaying a biological sample (e.g., comprising blood, (b) administering a treatment to the individual after the first time point and before the second time point, comprising one or more (e.g., two or more multiple, three or more, four or more, five or more or ten or more) doses of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof; (c) a second circulating tumor DNA level in a biological sample obtained from the individual at a second time point; and (d) determination of a second circulating tumor DNA level in individuals with a reduced level compared to the first circulating tumor DNA level. Resistance develops to the treatment; or an individual determined to have a second circulating tumor DNA level that is about the same or increased compared to the first circulating tumor DNA level develops resistance to the treatment. In some embodiments of these methods, the first time point is separated from the second time point by about 1 week to about 1 year (e.g., about 1 week to about 10 months, about 1 week to about 8 months, about 1 week to about 6 months months, about 1 week to about 4 months, about 1 week to about 3 months, about 1 week to about 2 months, about 1 week to about 1 month, or about 1 week to about 2 weeks).

Exemplary methods for detecting circulating tumor DNA are described in Moati et al., Clin. Res. Hepatol. Gastroenterol. Apr. 4, 2018; Oussalah et al., EBioMedicine Mar. 28, 2018; Moon et al., Adv. Drug Deliv. Rev. April 4, 2018; Solassaol et al., Clin. Chem. Lab. Med. April 7, 2018; Arriola et al., Clin. Transl. Oncol. April 5, 2018; Song et al. 25 March 2018; Aslibekyan et al., JAMA Cardiol. 4 April 2018; Isbell et al., J. Thorac. Cardiovasc. Surg. 13 March 2018; Boeckx et al. People, Clin. Colorectal Cancer 22 February 2018; Anunobi et al., J. Surg. Res. 28 March 2018; Tan et al., Medicine 97(13):e0197, 2018; Reithdorf et al., Transl. Androl. Urol. 6(6):1090-1110, 2017; Volckmar et al., Genes Chromosomes Cancer 57(3):123-139, 2018; and Lu et al., Chronic Dis. Transl. Med. 2(4): 223-230, 2016. Other methods for detecting circulating tumor DNA are known in the art.

In some embodiments, provided herein is a method of treating a RET-associated cancer in an individual in need of such treatment, the method comprising (a) detecting the expression of the RET gene, RET kinase, or either in a sample from the individual or a disorder of activity or content; and (b) administering to the individual a therapeutically effective amount of a multiple kinase inhibitor, wherein the multiple kinase inhibitor is selected from vandetanib or cabozantinib; or a pharmaceutically acceptable salt or solvate. In some embodiments, the methods further comprise (after (b)) (c) determining whether cancer cells in a sample obtained from the individual have at least one RET inhibitor resistance mutation; and (d) if the individual has For cancer cells with at least one RET inhibitor resistance mutation, a compound of formula I or a pharmaceutically acceptable salt or solvate thereof is administered to the individual as monotherapy or in combination with another anticancer agent; or (e ) if the individual has cancer cells that do not contain a RET inhibitor resistance mutation, then administering an additional dose of the multiple kinase inhibitor of step (b) to the individual.

In some embodiments, provided herein is a method of treating a RET-associated cancer in an individual in need of such treatment, the method comprising (a) detecting the expression of the RET gene, RET kinase, or either in a sample from the individual or a disorder in activity or level; and (b) administering to the individual a therapeutically effective amount of a first multiple kinase inhibitor, wherein the multiple kinase inhibitor is selected from the group consisting of vandetanib or cabozantinib; or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) determining whether cancer cells in a sample obtained from the individual have at least one RET inhibitor resistance mutation; and (d) if the individual has For cancer cells with at least one RET inhibitor resistance mutation, a compound of formula I selected from Examples 1-10, Examples 11-20, Examples 21-34 is administered to the individual as monotherapy or in combination with another anticancer agent or a pharmaceutically acceptable salt or solvate thereof; or (e) if the individual has cancer cells that do not contain a RET inhibitor resistance mutation, then administering to the individual an additional dose of the multiple kinase inhibitor of step (b) agent.

In some embodiments, provided herein is a method of treating a RET-associated cancer in an individual in need of such treatment, the method comprising (a) detecting one or more fusion proteins of Table 1 and/or a fusion protein of Table 1 in a sample from the individual or more of the RET kinase protein point mutations/insertions/deletions of Table 2; and (b) administering to the individual a therapeutically effective amount of a multiple kinase inhibitor, wherein the multiple kinase inhibitor is selected from the group consisting of vandetanib or Cabozantinib; or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) determining whether the cancer cells in the sample obtained from the individual have at least one RET inhibitor resistance mutation of Table 3 or 4; and (d ) if the subject has cancer cells containing at least one RET inhibitor resistance mutation, administering to the subject a group selected from Examples 1-10, Examples 11-20, Examples 21- as monotherapy or in combination with another anti-cancer agent A compound of formula I of 34, or a pharmaceutically acceptable salt or solvate thereof; or (e) if the individual has cancer cells that do not contain a RET inhibitor resistance mutation, the step of administering an additional dose to the individual (b ) multiple kinase inhibitors.

In some embodiments, provided herein is a method of treating a RET-associated cancer in an individual in need of such treatment, the method comprising (a) detecting the fusion protein KIF5B-RET in a sample from the individual; and (b) administering to the individual A therapeutically effective amount of a multiple kinase inhibitor is administered, wherein the multiple kinase inhibitor is selected from the group consisting of vandetanib or cabozantinib; or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) determining whether the cancer cells in the sample obtained from the individual have the RET inhibitor resistance mutation V804M, G810S, or G810R; and (d) if The subject has cancer cells containing at least one RET inhibitor resistance mutation, and the subject is administered an agent selected from Examples 1-10, Examples 11-20, Examples 21-34 as monotherapy or in combination with another anticancer agent. A compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable salt or solvate thereof; or (e) if the individual has cancer cells that do not contain a RET inhibitor resistance mutation, An additional dose of the multiple kinase inhibitor of step (b) is then administered to the individual.

As another example, provided herein are methods for treating RET-associated cancer in an individual in need of such treatment, the method comprising (a) detecting the RET gene, RET kinase, or either of them in a sample from the individual a disorder of expression or activity or level; and (b) administering to the individual a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) determining whether cancer cells in a sample obtained from the individual have at least one RET inhibitor resistance mutation; and (d) if the individual has Cancer cells with at least one RET inhibitor resistance mutation, then multiple kinase inhibitors (such as vandetanib or cabozantinib) are administered to the individual as monotherapy or in combination with another anticancer agent; or (e ) If the individual has cancer cells that do not contain a RET inhibitor resistance mutation, then administering to the individual an additional dose of the compound of formula I of step (b), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, provided herein are methods for treating a RET-associated cancer in an individual in need of such treatment, the method comprising (a) detecting the RET gene, RET kinase, or either of them in a sample from the individual and (b) administering a therapeutically effective amount of a compound of formula I selected from examples 1-10, examples 11-20, examples 21-34 or a pharmaceutically acceptable salt thereof or solvates. In some embodiments, the methods further comprise (after (b)) (c) determining whether cancer cells in a sample obtained from the individual have at least one RET inhibitor resistance mutation; and (d) if the individual has Cancer cells with at least one RET inhibitor resistance mutation, then multiple kinase inhibitors (such as vandetanib or cabozantinib) are administered to the individual as monotherapy or in combination with another anticancer agent; or (e ) If the individual has cancer cells that do not contain a RET inhibitor resistance mutation, then administering to the individual an additional dose of the compound of formula I of step (b), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, provided herein are methods for treating a RET-associated cancer in an individual in need of such treatment, the method comprising (a) detecting one or more fusion proteins of Table 1 in a sample from the individual and/or or one or more RET kinase protein point mutations/insertions/deletions of Table 2; and (b) administering a therapeutically effective amount of a compound of formula I selected from examples 1-10, examples 11-20, examples 21-34 or Its pharmaceutically acceptable salt or solvate. In some embodiments, the methods further comprise (after (b)) (c) determining whether the cancer cells in the sample obtained from the individual have at least one RET inhibitor resistance mutation of Table 3 or 4; and (d ) if the individual has cancer cells containing at least one RET inhibitor resistance mutation, administering multiple kinase inhibitors (such as vandetanib or cabozantinib) to the individual as monotherapy or in combination with another anticancer agent ); or (e) if the individual has cancer cells that do not contain a RET inhibitor resistance mutation, then administering an additional dose of the compound of formula I of step (b) or a pharmaceutically acceptable salt or solvate thereof to the individual things. In some embodiments, provided herein are methods for treating a RET-associated cancer in an individual in need of such treatment, the method comprising (a) detecting the fusion protein KIF5B-RET in a sample from the individual; and (b) A therapeutically effective amount of a compound of formula I selected from Examples 1-10, Examples 11-20, Examples 21-34, or a pharmaceutically acceptable salt or solvate thereof is administered to the individual. In some embodiments, the methods further comprise (after (b)) (c) determining whether the cancer cells in the sample obtained from the individual have the RET inhibitor resistance mutation V804M, G810S, or G810R; and (d) if The subject has cancer cells containing at least one RET inhibitor resistance mutation, then a multiple kinase inhibitor (eg, vandetanib or cabozantinib) is administered to the subject as monotherapy or in combination with another anticancer agent; Or (e) if the individual has cancer cells that do not contain a RET inhibitor resistance mutation, then administering to the individual an additional dose of the compound of formula I of step (b), or a pharmaceutically acceptable salt or solvate thereof.

Also, provided herein is a method of treating RET-associated cancers in an individual in need of such treatment, the method comprising (a) detecting the expression or activity or amount of the RET gene, RET kinase, or either of them in a sample from the individual and (b) administering to the individual a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) determining whether cancer cells in a sample obtained from the individual have at least one RET inhibitor resistance mutation; and (d) if the individual has Cancer cells with at least one RET inhibitor resistance mutation are treated with monotherapy or with another anticancer agent (such as a second RET inhibitor, a second compound of formula I or a pharmaceutically acceptable salt or solvate thereof, or immunotherapy) or anti-cancer therapy (such as surgery or radiation) in combination with re-administering an additional dose of the compound of formula I of step (b) or a pharmaceutically acceptable salt or solvate thereof to the individual. In some embodiments, provided herein are methods for treating a RET-associated cancer in an individual in need of such treatment, the method comprising (a) detecting the RET gene, RET kinase, or either of them in a sample from the individual and (b) administering a therapeutically effective amount of a compound of formula I selected from examples 1-10, examples 11-20, examples 21-34 or a pharmaceutically acceptable salt thereof or solvates. In some embodiments, the methods further comprise (after (b)) (c) determining whether cancer cells in a sample obtained from the individual have at least one RET inhibitor resistance mutation; and (d) if the individual has Cancer cells with at least one RET inhibitor resistance mutation are treated with monotherapy or with another anticancer agent (such as a second RET inhibitor, a second compound of formula I or a pharmaceutically acceptable salt or solvate thereof, or immunotherapy) or anti-cancer therapy (such as surgery or radiation) in combination with re-administering an additional dose of the compound of formula I of step (b) or a pharmaceutically acceptable salt or solvate thereof to the individual. In some embodiments, provided herein is a method of treating a RET-associated cancer in an individual in need of such treatment, the method comprising (a) detecting in a sample from the individual one or more fusion proteins of Table 1 and/or a or multiple RET kinase protein point mutations/insertions/deletions of Table 2; and (b) administering a therapeutically effective amount of a compound of formula I selected from examples 1-10, examples 11-20, examples 21-34 or a medicine thereof A pharmaceutically acceptable salt or solvate, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) determining whether the cancer cells in the sample obtained from the individual have at least one RET inhibitor resistance mutation of Table 3 or 4; and (d ) if the individual has cancer cells containing at least one RET inhibitor resistance mutation, in monotherapy or in combination with another anticancer agent (such as a second RET inhibitor, a second compound of formula I, or a pharmaceutically acceptable salt thereof or solvate, or immunotherapy) or anti-cancer therapy (such as surgery or radiation) combined with the form of re-administering an additional dose of the compound of formula I of step (b) or a pharmaceutically acceptable salt or solvate thereof to the individual things. In some embodiments, a second RET inhibitor is administered in step (d) selected from the group consisting of alectinib, cabozantinib, lenvatinib, nintedanib, purna Atinib, Regorafenib, Sorafenib, Sunitinib, Vandetanib, RXDX-105 (Grafenib), LOXO-292, BLU-667 ((1S,4R)-N-(( S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-(( 5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexane-1-carboxamide), BLU6864, DS-5010, GSK3179106, GSK3352589 and NMS-E668. In some embodiments, provided herein are methods for treating a RET-associated cancer in an individual in need of such treatment, the method comprising (a) detecting the fusion protein KIF5B-RET in a sample from the individual; and (b) A therapeutically effective amount of a compound of formula I selected from Examples 1-10, Examples 11-20, Examples 21-34, or a pharmaceutically acceptable salt or solvate thereof is administered to the individual. In some embodiments, the methods further comprise (after (b)) (c) determining whether the cancer cells in the sample obtained from the individual have the RET inhibitor resistance mutation V804M, G810S, or G810R; and (d) if Individuals with cancer cells containing at least one RET inhibitor resistance mutation are treated with monotherapy or with another anticancer agent (such as a second RET inhibitor, a second compound of formula I, or a pharmaceutically acceptable salt or solvent thereof) compound, or immunotherapy) or anti-cancer therapy (such as surgery or radiation) or anti-cancer therapy (such as surgery or radiation) combined with re-administering to the individual an additional dose of the compound of formula I of step (b), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a second RET inhibitor is administered in step (d) selected from the group consisting of alectinib, cabozantinib, lenvatinib, nintedanib, purna Atinib, Regorafenib, Sorafenib, Sunitinib, Vandetanib, RXDX-105 (Grafenib), LOXO-292, BLU-667 ((1S,4R)-N-(( S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-(( 5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexane-1-carboxamide), BLU6864, DS-5010, GSK3179106, GSK3352589 and NMS-E668.

Also, provided herein is a method of treating RET-associated cancers in an individual in need of such treatment, the method comprising (a) detecting the expression or activity or amount of the RET gene, RET kinase, or either of them in a sample from the individual and (b) administering to the individual a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) detecting at least one RET inhibitor resistance mutation in cancer cells in a sample obtained from the individual; and (d) administering monotherapy Or in combination with another anticancer agent (such as a second RET inhibitor, a second compound of formula I or a pharmaceutically acceptable salt or solvate thereof, or immunotherapy) or anticancer therapy (such as surgery or radiation) The compound of formula I of step (b) or a pharmaceutically acceptable salt or solvate thereof is re-administered to the individual in an additional dose. In some embodiments, provided herein are methods for treating a RET-associated cancer in an individual in need of such treatment, the method comprising (a) detecting the RET gene, RET kinase, or either of them in a sample from the individual and (b) administering a therapeutically effective amount of a compound of formula I selected from examples 1-10, examples 11-20, examples 21-34 or a pharmaceutically acceptable salt thereof or solvates. In some embodiments, the methods further comprise (after (b)) (c) detecting at least one RET inhibitor resistance mutation in cancer cells in a sample obtained from the individual; and (d) administering monotherapy Or in combination with another anticancer agent (such as a second RET inhibitor, a second compound of formula I or a pharmaceutically acceptable salt or solvate thereof, or immunotherapy) or anticancer therapy (such as surgery or radiation) The compound of formula I of step (b) or a pharmaceutically acceptable salt or solvate thereof is re-administered to the individual in an additional dose. In some embodiments, provided herein is a method of treating a RET-associated cancer in an individual in need of such treatment, the method comprising (a) detecting in a sample from the individual one or more fusion proteins of Table 1 and/or a or multiple RET kinase protein point mutations/insertions/deletions of Table 2; and (b) administering a therapeutically effective amount of a compound of formula I selected from examples 1-10, examples 11-20, examples 21-34 or a medicine thereof A pharmaceutically acceptable salt or solvate, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) detecting at least one RET inhibitor resistance mutation of Table 3 or 4 in cancer cells in a sample obtained from the individual; and ( d) as monotherapy or in combination with another anticancer agent (such as a second RET inhibitor, a second compound of formula I or a pharmaceutically acceptable salt or solvate thereof, or immunotherapy) or anticancer therapy (such as surgery or radiation) in combination with re-administering an additional dose of the compound of formula I of step (b) or a pharmaceutically acceptable salt or solvate thereof to the individual. In some embodiments, a second RET inhibitor is administered in step (d) selected from the group consisting of alectinib, cabozantinib, lenvatinib, nintedanib, purna Atinib, Regorafenib, Sorafenib, Sunitinib, Vandetanib, RXDX-105 (Grafenib), LOXO-292, BLU-667 ((1S,4R)-N-(( S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-(( 5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexane-1-carboxamide), BLU6864, DS-5010, GSK3179106, GSK3352589 and NMS-E668. In some embodiments, provided herein are methods for treating RET-associated cancer in an individual in need of such treatment, the method comprising (a) detecting the fusion protein KIF5B-RET in a sample from the individual; and (b) A therapeutically effective amount of a compound of formula I selected from Examples 1-10, Examples 11-20, Examples 21-34, or a pharmaceutically acceptable salt or solvate thereof is administered to the individual. In some embodiments, the methods further comprise (after (b)) (c) detecting the RET inhibitor resistance mutation V804M, G810S, or G810R in cancer cells in a sample obtained from the individual; and (d) As monotherapy or in combination with another anticancer agent (such as a second RET inhibitor, a second compound of formula I or a pharmaceutically acceptable salt or solvate thereof, or immunotherapy) or anticancer therapy (such as surgery or radiation ) and administering an additional dose of the compound of formula I of step (b) or a pharmaceutically acceptable salt or solvate thereof to the individual in combination. In some embodiments, a second RET inhibitor is administered in step (d) selected from the group consisting of alectinib, cabozantinib, lenvatinib, nintedanib, purna Atinib, Regorafenib, Sorafenib, Sunitinib, Vandetanib, RXDX-105 (Grafenib), LOXO-292, BLU-667 ((1S,4R)-N-(( S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-(( 5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexane-1-carboxamide), BLU6864, DS-5010, GSK3179106, GSK3352589 and NMS-E668.

The present invention also provides a method for treating lung cancer in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, crizotinib, Osimertinib or any combination thereof.

In some embodiments, the lung cancer is a RET-associated cancer. For example, the method may comprise: (a) detecting a disorder in the expression or activity or level of the RET gene, RET kinase, or either in a sample from an individual; and (b) administering to the individual a therapeutically effective amount A compound of formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) determining whether the cancer cells in the sample obtained from the individual have at least one RET inhibitor resistance mutation (e.g., MET dysregulation, such as a MET gene amplification and (d) if the individual has cancer cells containing at least one RET inhibitor resistance mutation, administering to the individual as monotherapy or in combination with a compound of formula I or a pharmaceutically acceptable salt or solvate thereof administering a second therapeutic agent, wherein the second therapeutic agent is crizotinib; or (e) if the individual has cancer cells that do not contain a RET inhibitor resistance mutation, then administering to the individual an additional dose of step (b) A compound of formula I or a pharmaceutically acceptable salt or solvate thereof. In some such embodiments, the method comprises (a) detecting a point mutation/insertion in one or more fusion proteins of Table 1 and/or one or more RET kinase proteins of Table 2 in a sample from an individual; and (b ) administering to a subject a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the methods further comprise (after (b)) (c) determining whether the cancer cells in the sample obtained from the individual have at least one RET inhibitor resistance mutation (e.g., MET dysregulation, such as a MET gene amplification and (d) if the individual has cancer cells containing at least one RET inhibitor resistance mutation, administering to the individual as monotherapy or in combination with a compound of formula I or a pharmaceutically acceptable salt or solvate thereof administering a second therapeutic agent, wherein the second therapeutic agent is crizotinib; or (e) if the individual has cancer cells that do not contain a RET inhibitor resistance mutation, then administering to the individual an additional dose of step (b) A compound of formula I or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, the lung cancer is an EGFR-related cancer. For example, the method may comprise: (a) detecting a disorder in the expression or activity or level of the EGFR gene, EGFR kinase, or either in a sample from an individual; and (b) administering to the individual a therapeutically effective amount EGFR inhibitors (such as osimertinib). In some embodiments, the methods further comprise (after (b)) (c) determining whether the cancer cells in the sample obtained from the individual have expression or activity or levels of the RET gene, RET kinase, or either ( at least one disorder of, for example, a RET gene fusion); and (d) if the individual has cancer cells containing at least one disorder of the expression or activity or level of the RET gene, RET kinase, or either (e.g., a RET gene fusion), The compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, is then administered to the subject as monotherapy or in combination with an EGFR inhibitor (eg, osimertinib); or (e) if the subject has RET-free gene, RET kinase, or at least one dysregulated expression or activity or level of any of them (such as a RET gene fusion), then an additional dose of the EGFR inhibitor of step (b) (such as Austrian Hirtinib). In some such embodiments, the method comprises (a) detecting a dysregulation of the expression or activity or level of the EGFR gene, EGFR kinase, or either in a sample from the individual; and (b) administering the treatment to the individual An effective amount of osimertinib. In other embodiments, the methods further comprise (after (b)) (c) determining whether cancer cells in a sample obtained from the individual have one or more fusion proteins of Table 1 and/or one or more fusion proteins of Table 2 RET kinase protein point mutations/insertions; and (d) if the individual has cancer cells containing one or more fusion proteins of Table 1 and/or one or more RET kinase protein point mutations/insertions of Table 2, either as monotherapy or with The combined form of osimertinib is administered to the individual with a compound of formula I or a pharmaceutically acceptable salt or solvate thereof; or (e) if the individual has a fusion protein that does not contain one or more of Table 1 and/or one or For cancer cells with a variety of RET kinase protein point mutations/insertions in Table 2, an additional dose of osimertinib in step (b) was administered to the individual.

As used herein, the term "EGFR-associated cancer" refers to a cancer that is associated with or has an expression or activity of the EGFR gene, EGFR kinase, or any of them. Or cancers with imbalanced content.

Also provided are methods of selecting treatment for an individual with cancer comprising: identifying an individual having cancer cells containing one or more RET inhibitor resistance mutations; and selecting a treatment comprising administering a compound of Formula I or a pharmaceutical thereof Pharmaceutically acceptable salts or solvates. In some embodiments, one or more RET inhibitor resistance mutations confer increased resistance to cancer cell or tumor to treatment with a first RET inhibitor. In some embodiments, a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, is administered in combination with a first RET inhibitor. Also provided is a method of selecting for treatment of an individual with cancer comprising: for an individual identified as having cancer cells containing one or more RET inhibitor resistance mutations, selecting comprising administering a compound of Formula I or its pharmaceutically Treatment of acceptable salts or solvates. Also provided is a method of selecting an individual with cancer for treatment that does not include a first RET inhibitor as monotherapy, the method comprising: identifying an individual with cancer cells containing one or more RET inhibitor resistance mutations; and selecting the identified individual for treatment comprising a compound of formula I or a pharmaceutically acceptable salt or solvate thereof. Also provided is a method of selecting an individual with cancer for treatment that does not include a first RET inhibitor as monotherapy, the method comprising: selecting a cancer cell identified as having one or more RET inhibitor resistance mutations The individual is subjected to treatment comprising administering a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the one or more RET inhibitor resistance mutations include one or more RET inhibitor resistance mutations listed in Tables 3 and 4. In some embodiments, one or more RET inhibitor resistance mutations may include a substitution at amino acid position 804, such as V804M, V804L, or V804E, or a substitution at amino acid position 810, such as G810S, G810R, G810C, G810A, G810V and G810D.

Also provided is a method of determining the likelihood that an individual with cancer (e.g., a RET-associated cancer) will respond positively to treatment with a first RET inhibitor as monotherapy comprising: determining the cancer in a sample obtained from the individual whether the cells have one or more RET inhibitor resistance mutations; and determining that individuals with cancer cells containing one or more RET inhibitor resistance mutations have reduced susceptibility to treatment with a first RET inhibitor as monotherapy The likelihood of a positive response (ie, the increased likelihood of having a negative response). Also provided is a method of determining the likelihood that an individual with cancer (e.g., a RET-associated cancer) will respond positively to treatment with a first RET inhibitor as monotherapy comprising: determining the cancer in a sample obtained from the individual whether the cells have one or more RET inhibitor resistance mutations; and determining whether individuals who do not have cancer cells that contain one or more RET inhibitor resistance mutations are compared to individuals who have cancer cells that contain one or more RET inhibitor resistance mutations The ratio has an increased likelihood of having a positive response to treatment with the first RET inhibitor as monotherapy. Also provided are methods of predicting the efficacy of treatment with a first RET inhibitor as monotherapy in an individual with cancer comprising: determining whether cancer cells in a sample obtained from the individual have one or more RET inhibitors resistance mutations; and determining that treatment with a first RET inhibitor as monotherapy is unlikely to be effective in an individual with cancer cells in a sample obtained from the individual that have one or more RET inhibitor resistance sexual mutation. Also provided are methods of predicting the efficacy of treatment with a first RET inhibitor as monotherapy in an individual with cancer comprising: determining that treatment with the first RET inhibitor as monotherapy is unlikely Effective in an individual having cancer cells in a sample obtained from the individual, the cancer cells having one or more RET inhibitor resistance mutations. In some embodiments, one or more RET inhibitor resistance mutations confer increased resistance to cancer cell or tumor to treatment with a first RET inhibitor. In some embodiments, the one or more RET inhibitor resistance mutations include one or more RET inhibitor resistance mutations listed in Tables 3 and 4. For example, one or more RET inhibitor resistance mutations can include a substitution at amino acid position 804, such as V804M, V804L, or V804E, or a substitution at amino acid position 810, such as G810S, G810R, G810C, G810A, G810V and G810D.

Also provided are methods of treating an individual with cancer comprising: (a) administering to the individual one or more doses of a first RET inhibitor for a period of time; (b) after (a), determining the RET inhibitor obtained from the individual whether the cancer cells in the sample have at least one RET inhibitor resistance mutation; and (c) if the individual has cancer cells that contain at least one RET inhibitor resistance mutation, as monotherapy or in combination with another anticancer agent The step of administering to the individual a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof; or (d) if the individual has cancer cells that do not contain a RET inhibitor resistance mutation, then administering an additional dose to the individual (a) The first RET inhibitor. In some embodiments, when an additional dose of the first RET inhibitor of step (a) is administered to the individual, another anticancer agent (such as a second RET inhibitor or a compound of formula I or its pharmaceutically acceptable salt or solvate, or immunotherapy). In some embodiments, the other anticancer agent is any anticancer agent known in the art. For example, the additional anticancer agent can be another RET inhibitor (eg, a second RET inhibitor). In some embodiments, the other anticancer agent may be immunotherapy. In some embodiments of step (c), the second RET inhibitor can be the first RET inhibitor administered in step (a). In some embodiments, one or more RET inhibitor resistance mutations confer increased resistance to cancer cell or tumor to treatment with a first RET inhibitor. In some embodiments, the one or more RET inhibitor resistance mutations include one or more RET inhibitor resistance mutations listed in Tables 3 and 4. For example, one or more RET inhibitor resistance mutations can include a substitution at amino acid position 804, such as V804M, V804L, or V804E, or a substitution at amino acid position 810, such as G810S, G810R, G810C, G810A, G810V and G810D.

Also provided are methods of treating an individual with cancer comprising: (a) administering to the individual one or more doses of a first RET inhibitor for a period of time; (b) after (a), determining the RET inhibitor obtained from the individual whether the cancer cells in the sample have at least one RET inhibitor resistance mutation; and (c) if the individual has cancer cells that contain at least one RET inhibitor resistance mutation, either as monotherapy or in combination with another anticancer agent or (d) if the individual has cancer cells that do not contain a RET inhibitor resistance mutation, then administering an additional dose of the first RET inhibitor of step (a) to the individual . In some embodiments, when an additional dose of the first RET inhibitor of step (a) is administered to the individual, another anti-cancer agent may also be administered to the individual. In some embodiments, one or more RET inhibitor resistance mutations confer increased resistance to cancer cell or tumor to treatment with a first RET inhibitor. In some embodiments, the one or more RET inhibitor resistance mutations include one or more RET inhibitor resistance mutations listed in Tables 3 and 4. For example, one or more RET inhibitor resistance mutations can include a substitution at amino acid position 804, such as V804M, V804L, or V804E, or a substitution at amino acid position 810, such as G810S, G810R, G810C, G810A, G810V and G810D. In some embodiments, the other anticancer agent is any anticancer agent known in the art. For example, the other anticancer agent is another RET inhibitor (such as a compound of formula I or a pharmaceutically acceptable salt or solvate thereof). In some embodiments, the other anticancer agent is immunotherapy.

Also provided are methods of treating an individual with cancer (e.g., a RET-associated cancer), comprising: (a) assaying for the presence of α in a sample obtained from an individual with cancer who has previously been administered one or more doses of a first RET inhibitor. whether the individual's cancer cells have one or more RET inhibitor resistance mutations; and (b) if the individual has cancer cells containing at least one RET inhibitor resistance mutation, to The subject is administered a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof; or (c) if the subject has cancer cells that do not contain a RET inhibitor resistance mutation, then administering to the subject an additional dose of previously administered A first RET inhibitor is administered. In some embodiments, another anti-cancer agent (e.g., a compound of formula I or a pharmaceutically acceptable salt thereof) may also be administered to the subject while other doses of the first RET inhibitor have been previously administered to the subject. or solvates, or immunotherapy). In some embodiments, one or more RET inhibitor resistance mutations confer increased resistance to cancer cell or tumor to treatment with a first RET inhibitor. In some embodiments, the one or more RET inhibitor resistance mutations include one or more RET inhibitor resistance mutations listed in Tables 3 and 4. For example, one or more RET inhibitor resistance mutations can include a substitution at amino acid position 804, such as V804M, V804L, or V804E, or a substitution at amino acid position 810, such as G810S, G810R, G810C, G810A, G810V and G810D. In some embodiments, the other anticancer agent is any anticancer agent known in the art. For example, the additional anticancer agent can be another RET inhibitor (eg, a second RET inhibitor). In some embodiments, the other anticancer agent may be immunotherapy. In some embodiments of step (b), the other anticancer agent may be the first RET inhibitor administered in step (a).

Also provided are methods of treating an individual with cancer comprising: (a) determining whether cancer cells in a sample obtained from an individual with cancer who have previously been administered one or more doses of a first RET inhibitor have a or more RET inhibitor resistance mutations; and (b) if the individual has cancer cells containing at least one RET inhibitor resistance mutation, administering a second RET to the individual as monotherapy or in combination with another anticancer agent inhibitor; or (c) if the individual has cancer cells that do not contain a RET inhibitor resistance mutation, then administering to the individual an additional dose of the first RET inhibitor that was previously administered. In some embodiments, another anti-cancer agent may also be administered to the subject when the subject is re-administered an additional dose of the first RET inhibitor that was previously administered. In some embodiments, one or more RET inhibitor resistance mutations confer increased resistance to cancer cell or tumor to treatment with a first RET inhibitor. In some embodiments, the one or more RET inhibitor resistance mutations include one or more RET inhibitor resistance mutations listed in Tables 3 and 4. For example, one or more RET inhibitor resistance mutations can include a substitution at amino acid position 804, such as V804M, V804L, or V804E, or a substitution at amino acid position 810, such as G810S, G810R, G810C, G810A, G810V and G810D. In some embodiments, the other anticancer agent is any anticancer agent known in the art. For example, the other anticancer agent is another RET inhibitor (such as a compound of formula I or a pharmaceutically acceptable salt or solvate thereof). In some embodiments, the other anticancer agent is immunotherapy. In some embodiments of (b), the other anticancer agent may be the first RET inhibitor administered in step (a).

In some embodiments, a RET-associated cancer as described herein and another gene, another protein, or a dysregulation of the expression or activity or level of any of these may be present in the individual.

For example, a RET-associated cancer exhibiting a RET fusion and one or more of: MET gene, MET protein, or a dysregulation of expression or activity or amount of either; PIK3CA gene, PIK3CA protein, or Disregulation of expression or activity or content of any of them; Disregulation of expression or activity or content of KRAS gene, KRAS protein, or any of them; Disorder of expression, activity or content of EGFR gene, EGFR protein, or any of them (such as the amplification of EGFR gene); the expression or activity or content of FGFR2 gene, FGFR2 protein or any of them are disordered (such as the fusion of FGFR2 gene or FGFR2 protein); CDK4 gene, CDK4 protein or any of them Disregulation of expression or activity or content (such as amplification of CDK4 gene); dysregulation of expression or activity or content of mTOR gene, protein or any of them; expression or activity or content of CDKN2A gene, CDKN2A protein or any of them Disregulation (such as loss of CDKN2A gene or CDKN2A protein); CDKN2B gene, CDKN2B protein or any one of the expression or activity or content of the disorder (such as CDKN2B gene or CDKN2B protein loss); NF1 gene, NF1 protein or any of them Disregulation of expression or activity or content of one; Disregulation of expression or activity or content of MYC gene, MYC protein, or any of them (such as amplification of MYC gene); Expression of MDM2 gene, MDM2 protein, or any of them Disregulation of expression or activity or content of GNAS gene, GNAS protein, or any of them (such as amplification of MDM2 gene); expression or activity or content of BRCA2 gene, BRCA2 protein, or of any of them Disregulation of EHMT2 gene, EHMT2 protein, or expression or activity or content of any of them; SOS1 gene, SOS1 protein, or expression or activity or content of any of them.

In some embodiments, a RET-associated cancer exhibiting a mutation in the RET gene and/or RET protein and one or more of the following: PIK3CA gene, PIK3CA protein, or expression or activity or level of any of them may be present in the individual. Dysregulation; KRAS gene, KRAS protein or any one of the expression or activity or content of the disorder; EGFR gene, EGFR protein or any one of the expression or activity or content of the disorder; FGFR1 gene, FGFR1 protein any of them Disregulation of expression or activity or content (such as amplification of FGFR1 gene); FGFR2 gene, FGFR2 protein, or expression or activity or content of any of them (such as amplification of FGFR2 gene); FGFR3 gene, FGFR3 protein or any of them Dysregulation of the expression or activity or level of either (eg FGFR3 gene or fusion of FGFR3 protein); ERBB2 (also known as HER2) gene, ERBB2 protein or expression or activity or level of either (eg ERBB2 gene Amplification); and KIT gene, KIT protein or any one of the expression or activity or content of the disorder.

In some embodiments, a RET-associated cancer exhibiting amplification of the RET gene and amplification of one or more other kinases may be present in the patient. For example, amplification of the FGFR1 gene; amplification of the FGFR2 gene; amplification of the FGFR3 gene; amplification of the FGFR4 gene; amplification of the CDK4 gene;

In some embodiments, where a RET-associated cancer as described herein and dysregulation of another kinase may be present in an individual, the methods described herein may further comprise administering other agents that target and/or treat the other kinase A cure for disorders. For example, provided herein is a method of treating a RET-associated cancer in an individual in need of such treatment, the method comprising (a) detecting the expression or activity of the RET gene, RET kinase, or either in a sample from the individual or an imbalance in its content; and (b) administering to the individual a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the method further comprises (c) detecting a dysregulation of another kinase in a sample from the individual; and (d) administering to the individual a therapeutic agent that targets and/or treats the dysregulation of the other kinase . In some embodiments, the administration of the compound of formula I or a pharmaceutically acceptable salt or solvate thereof is performed simultaneously, sequentially or continuously. In some embodiments, detection steps (a) and (c) can be performed simultaneously or sequentially in any order.

Other therapeutic agents that target and/or treat the dysregulation of another kinase may include any known inhibitor of another kinase. Examples of such agents are as follows:

Exemplary PARP inhibitors include: 3-aminobenzamide (INO-1001), 5-aminoisoquinoline, ABT472, ABT767, AG140361, AG14032, ANG2864, ANG3186, AZD2281, AZD2461, BGP-15, BSI101 , BSI401, CEP6800, CEP8983, CK102, CEP9722 (predrug of CEP8983), CPH101 combined with CPH102, DR2313, E7016 (GPI-21016), E7449, GP16150, IMP4297, IMP04149, INO1002, INO1003, JPI 283, JPI289, KU0687, KU58948, Nigeria Niraparib (MK-4827), NT125, Olaparib (AZD2281), ONO-1924H, ONO2231, Pamiparib (BGB-290), PJ-34, Ruka Rucaparib (AG014699), SC10914, SOMCL9112, talazoparib (BMN-673) and veliparib (ABT-888).

Exemplary CDK 4/6 inhibitors include: palbociclib (PD0332991), abemaciclib (LY2835219), ribociclib (LEE011), trilaciclib (G1T28 ), voruciclib and G1T38.

Exemplary ERBB2 (HER2/neu) inhibitors include: afatinib, afatinib, dacomitinib (PF-00299804), DS8201-a, erlontinib, Gefitinib, KU004, lapatinib, lapatinib ditosylate, MM-111, mubritinib (TAK-165), neratinib ), pyrotinib (HTI-1001), tucatinib (ONT-380, ARRY-380), 7C3, cetuximab, HER2-BsAb, Hesinmon Hersintuzumab, margetuximab, MI130004, NeuVax, paitumumab, pertuzumab, SYD985, trastuzumab, and trastuzumab Anti emtansine (trastuzumab emtansine).

Exemplary inhibitors of amplified ERBB2 (HER2/neu) include dacomitinib (PF-00299804), lapatinib, neratinib, pertuzumab, trastuzumab, and trastuzumab zizumab emtaxin.

Exemplary EGFR inhibitors include: AC0010, afatinib, AP26113, ASP8273, avatinib, avitinib, AZD3759, BMS-690514, brigatinib , canertinib, Cap-701, CHMFL-EGFR-202, CUDC-101, dacomitinib, EAI045, EGF816, erlontinib, erlotinib , gefitinib, GNS-1481, GNS-1486, Gö6976, HS-10296, icotinib, KU004, lapatinib, nazartinib, Neratinib, olmutinib (HM61713, BI 1482694), osimertinib, osimertinib (AZD9291), pelitinib, PF-06747775, PKC412 , pyrotinib (HTI-1001), rocilentinib, vandetanib, varlitinib, XL647, 7C3, cetuximab , depatuxizumab mafodotin (ABT-414), matuzumab, nimotuzumab, panitumumab and zalu Zalutumumab.

Exemplary wild-type EGFR inhibitors include: afatinib, BMS-690514, canertinib, CUDC-101, dacomitinib, erlotinib, gefitinib, lapatinib, neratinib Nimotuzumab, Pelitinib, Vandetanib, Vanitinib, XL647, Cetuximab, Matuzumab, Nimotuzumab, Panitumumab, and Zarumumab.

Exemplary inhibitors of mutant EGFR include: AC0010, afatinib, AP26113, ASP8273, avatinib, avitinib, AZD3759, BMS-690514, brigatinib, canertinib, Cap-701 , CHMFL-EGFR-202, CUDC-101, Dacomitinib, EAI045, EGF816, GNS-1481, GNS-1486, Gö6976, HS-10296, Icotinib, Nazatinib, Neratinib, Oxen Motinib (HM61713, BI 1482694), Osimertinib (AZD9291), PF-06747775, PKC412, Roxitinib, Vandetanib, Vanitinib and Cetuximab.

An exemplary inhibitor of amplified EGFR is deppartuxizumab mavodotan (ABT-414).

Exemplary inhibitors of FGFR include: ASP5878, AZD4547, BGJ398, BLU9931, brivatinib, cediranib, DEBIO 1347, derazantinib (ARQ-087), dovir tinib (CHIR258), E7090, ENMD-2076, erdafitinib (JNJ-42756293), FGF 401, FIIN-1, FRIN-1, INCB054828, L16H50, lenvatinib, lucitambu ( lucitanib), LY2874455, nintedanib, NP603, orantinib (SU6668), pazopanib, PBI05204, PD173074, ponatinib, PRN1371, regorafenib, rogatinib (rogaratinib)(BAY-1163877), S49076, SOMCL-085, SU5402, sunitinib, TAS-120, FP-1039, GAL-F2, GAL-FR21, GAL-FR22, GAL-FR23, GP369, hLD1. vb, LD1, MFGR1877S, MM-161, PRO-001 and R3Mab.

Exemplary inhibitors of FGFR fusions include: BGJ398, DEBIO 1347, dezatinib (ARQ-087), E7090, erdafitinib (JNJ-42756293), lucitamp, and TAS-120.

Exemplary inhibitors of FGFRl, FGFR2, and FGFR3 include: AZD4547, BGJ398, DEBIO 1347, E7090, INCB054828, S49076, SOMCL-085, and TAS-120.

Exemplary inhibitors of FGF4 include: BLU-554, BLU9931, NVP-FGF401 and hLD1.vb.

Exemplary inhibitors of amplified FGFRl include: AZD4547, BGJ398, DEBIO 1347, dezatinib (ARQ-087), erdafitinib (JNJ-42756293), INCB054828, and lucitamp.

Exemplary inhibitors of amplified FGFR2 include: AZD4547, DEBIO 1347, dezantinib (ARQ-087), lucitambu, regorafenib, and TAS-120.

An exemplary inhibitor of amplified FGFR3 is AZD4547.

Exemplary MEK inhibitors include: AZD8330 (ARRY-424704), AZD6244 (ARRY-142866), BI-847325, binitinib, BIX02188, BIX02189, CH4987655, CH5126766, CI-1040, cobemetinib) (GDC-0973), EBI-1051, G-573, G8935, GDC-0623, Myricetin, nobiletin, PD0325901, PD184161, PD318088, PD98059, PD334581, Pimaserti ( pimasertib) (AS-703026), refametinib (RDEA119, BAY 869766), selumetinib (AZD6244), SL-327, TAK-733, trametinib and U0126.

Exemplary KRAS inhibitors include: 0375-0604 (a quinazoline-based covalent switch II pocket (SIIP) compound), ARS-1620, AZD4785, and LP1.

Exemplary PI3K inhibitors include: 3-methyladenine, A66, alpelisib (BYL719), AMG319, aptolisib (GDC-0980, RG7422), AS-252424, AS- 604850, AS-605240, AZD6842, AZD8186, AZD8835, BGT226 (NVP-BGT226), Buparlisib (BKM120), CAY10505, CH5132799, Copanlisib (BA) (BA) (BA) (BA) Y 80-6946), CUDC- 907, CZC24832, dactolisib (BEZ235, NVP-BEZ235), DS7423, duvelisib (IPI-145, INK1197), GDC-0032, GDC-0084, GDC-0326, Gedazib Gedatolisib (PF-05212384, PKI-5587), GNE-317, GS-9820, GSK1059615, GSK2292767, GSK2636771, HS-173, IC-87114, Idelalisib (CAL-101, GS- 1101), IPI-145, IPI-3063, IPI-549, LY294002, LY3023414, Nemiralisib (GSK2269557), Omipalisib (GSK26458), PF-046915) 02, PF-4989216 , PI-103, PI-3065, pictilisib (GDC-0941), PIK-293, PIK-294, PIK-75, PIK-90, PIK-93, PIK-III, Piracoxib (pilaralisib)(XL147), PKI-587, PP-110, PQR309, PQR309, PW-12, PX-866, quercetin, S14161, SAR245409 (XL765), SAR260301, SAR405, ceracoxib ( serabelisib) (INK-1117, MLN-1117, TAK-1117), SF-1126, SF-2523, SN32976, taselisib (GDC-0032), TB101110, TG100-115, TG100-713, TGR -1202, TGX-221, umbralisib (TGR-1202), voxtalisib (XL765, SAR245409), VPS34-IN1, VS-5584 (SB2343), WJD008, wortmannin ( wortmannin) and ZSTK474.

Exemplary KIT inhibitors include: AMG 706, amuvatinib (MP-470), APcK110, axitinib (AG-013736), AZD2932, dasatinib ((BMS -354825), dovitinib (TKI-258, CHIR-258), EXEL-0862, imatinib, KI-328, masitinib (AB1010), midostaurin , MLN518, motesanib, N3-(6-aminopyridin-3-yl)-N1-(2-cyclopentylethyl)-4-methylisophthalamide, Nile Nilotinib, OSI-930, pazopanib (GW786034), pexidartinib (PLX3397), PKC412, PLX647, PP1, quizartinib (AC220), regorafenib (BAY 73-4506), sematinib (SU 5416), stetinib (MGCD516), sorafenib, STI571, SU11248, SU9529, sunitinib, telatinib, Tivozani (tivozanib) (AV-951), Tyrphostin AG 1296 (tyrphostin AG 1296), VX-322 and WBZ_4.

Exemplary MDM2 inhibitors include: (-)-parthenolide, ALRN6924, AM-8553, AMG232, CGM-097, DS-3032b, GEM240, HDM201, HLI98, idasanutlin (RG- 7338), JapA, MI-219, MI-219, MI-319, MI-77301(SAR405838), MK4828, MK-8242, MX69, NSC 207895 (XI-006), Nutlin-3 (Nutlin-3) , Nutrin-3a, Nutrin-3b, NVP-CFC218, NVP-CGM097, PXn727/822, RG7112, RO2468, RO5353, RO5503781, Serdemetan (JNJ-26854165), SP-141 and YH239-EE.

Exemplary inhibitors of amplified MDM2 include: AM-8553, AMG232, DS-3032b, MI-77301 (SAR405838), NSC 207895 (XI-006), Nutrin-3a, NVP-CFC218, NVP-CGM097 , and RG7112.

Exemplary inhibitors of MET include: (-)-Oleocanthal, ABBV-399, AMG-208, AMG-337, AMG-458, BAY-853474, BMS-754807, BMS-777607, BMS- 794833, cabozantinib (XL184, BMS-907351), capmatinib (INCB28060), crizotinib (PF-02341066), DE605, foretinib ( GSK1363089, XL880), glesatinib (MGCD265), golvatinib (E7050), INCB028060, JNJ-38877605, KRC-408, meretinib (LY2801653), MK- 2461, MK8033, NPS-1034, NVP-BVU972, PF-04217903, PHA-665752, S49076, Savolitinib (AZD6094, HMPL-504), SGX-523, SU11274, TAS-115, Tepredidine Tepotinib (EMD 1214063, MSC2156119J), volitinib, CE-355621 and Onartuzumab.

Exemplary inhibitors of mTOR include: anthracimycin, apitolisib (GDC-0980, RG7422), AZD-8055, BGT226 (NVP-BGT226), CC-223, CZ415, datoxib (dactolisib) (BEZ235, NVP-BEZ235), DS7423, everolimus (RAD001), GDC-0084, GDC-0349, gedatolisib (PF-05212384, PKI-5587), GSK1059615, Ink128, KU -0063794, LY3023414, MLN0128, Omipalisib (GSK2126458, GSK458), OSI-027, OSU-53, Palomid 529 (P529), PF-04691502, PI-103, PKI, PKI -587, PP242 , PQR309, ridafarolimus (AP-23573), sapanisertib (INK 128, MLN0128), SAR245409 (XL765), SF-1126, SF2523, sirolimus (sirolimus) (Ray Rapamycin), SN32976, TAK228, temsirolimus (CCI-779, NSC 683864), Torin 1, Torin 2, torkinib (PP242) , umirolimus, vistusertib (AZD2014), voxtalisib (XL765, SAR245409), VS-5584, VS-5584 (SB2343), WAY-600, WYE- 125132 (WYE-132), WYE-354, WYE-687, XL388, and zotarolimus (ABT-578).

Exemplary inhibitors of MYC include: 10058-F4, 10074-G5 and KSI-3716.

Exemplary EHMT2 inhibitors include: 2-(4,4-difluoropiperidin-1-yl)-N-(1-isopropylpiperidin-4-yl)-6-methoxy-7-(3 -(pyrrolidin-1-yl)propoxy)quinazolin-4-amine; 2-(4-isopropyl-1,4-benzodiazepine-1-yl)-N-(1-iso Propylpiperidin-4-yl)-6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinazolin-4-amine; A-366; BIX-01294 (BIX ); BIX-01338; BRD4770; DCG066; EZM8266; N-(1-isopropylpiperidin-4-yl)-6-methoxy-2-(4-methyl-1,4-diazacyclo Heptan-1-yl)-7-(3-(piperidin-1-yl)propoxy)quinazolin-4-amine; UNC0224; UNC0321; UNC0631; UNC0638 (2-cyclohexyl-6-methoxy Base-N-[1-(1-methylethyl)-4-piperidinyl]-7-[3-(1-pyrrolidinyl)propoxy]-4-quinazolinamine); UNC0642 ( 2-(4,4-difluoro-1-piperidinyl)-6-methoxy-N-[1-(1-methylethyl)-4-piperidinyl]-7-[3-( 1-pyrrolidinyl)propoxy]-4-quinazolinamine); and UNC0646. Other examples of EHMT2 inhibitors are known in the art.

Exemplary SOS1 inhibitors include those disclosed in PCT Publication No. WO 2018/115380, which is incorporated herein by reference. Other examples of SOS1 inhibitors are known in the art.

The phrase "disregulation of the expression or activity or content of a kinase gene, a kinase protein, or any of them" refers to a genetic mutation (such as a chromosomal translocation causing expression of a fusion protein comprising a kinase domain and a fusion partner, causing a protein comprising at least one Kinase gene mutations that cause expression of proteins with amino acid deletions (compared to wild-type kinase proteins), kinase gene mutations that cause expression of kinase proteins with one or more point mutations (compared to wild-type kinase proteins), cause Kinase gene mutations, gene duplications that result in increased levels of kinase proteins in cells, or regulatory sequences that result in increased levels of kinase proteins in cells with expression of a kinase protein with at least one inserted amino acid compared to wild-type kinase protein (e.g., promoter and/or enhancer mutations), alternative splicing forms of mRNA that produce a kinase protein that has at least one amino acid missing in the kinase protein (compared to the wild-type kinase protein), or due to abnormal cell signaling and/or increased expression (eg, increased levels) of wild-type kinase kinase in mammalian cells (eg, compared to control non-cancerous cells) caused by dysregulation of autocrine/paracrine signaling. As another example, a dysregulation of the expression or activity or level of a kinase gene, a kinase protein, or either may be a mutation in a kinase gene that encodes a kinase that is constitutively active or compared to that produced by a kinase that does not include the mutation. The protein encoded by the gene is a kinase protein with increased activity. For example, dysregulation of the expression or activity or level of a kinase gene, a kinase protein, or any of these may be the result of a gene or chromosomal translocation that results in the expression of a fusion protein comprising a functional The first part of the kinase protein and the second part of the partner protein (ie, not the main protein) of the sex kinase domain. In some instances, dysregulation of the expression or activity or level of a kinase gene, a kinase protein, or either may be the result of a genetic translocation of one kinase gene with a different gene. In some such embodiments the kinase is selected from the group consisting of ALK, BRAF, CDK4, EGFR, FGFR1, FGFR2, FGFR3, HER2, KIT, MEK, MET, mTOR, PIK3CA, RAF, and ROS1.

The phrase "dysregulation of the expression or activity or level of a non-kinase gene, a non-kinase protein, or either" refers to a genetic mutation (such as a chromosomal mutation that causes expression of a fusion protein comprising domains of a non-kinase protein and a fusion partner) Translocation, mutation of a non-kinase gene causing expression of a non-kinase protein comprising a deletion of at least one amino acid (compared to wild-type protein), causing a non-kinase protein with one or more point mutations (compared to wild-type protein) ), mutations in genes that cause expression of non-kinase proteins with at least one inserted amino acid (compared to wild-type non-kinase proteins), mutations that cause expression of non-kinase proteins in cells Gene duplications with altered levels or mutations in regulatory sequences (such as promoters and/or enhancers) that cause changes in the levels of non-kinase proteins in cells), cause deletions of at least one amino acid in non-kinase proteins (compared to wild-type non-kinase protein) or in mammalian cells caused by abnormal cell signaling and/or dysregulation of autocrine/paracrine signaling (e.g., compared to control non-kinase cells) Expression changes (for example, content changes) of wild-type non-kinase proteins. In some embodiments, the altered level of the non-kinase protein in the cell can be an increased level of the non-kinase protein in the cell. For example, dysregulation of non-kinase oncogenes can lead to increased levels of oncogenic non-kinase proteins in cells. In some embodiments, the altered level of the non-kinase protein in the cell can be a decrease in the level of the non-kinase protein in the cell. For example, dysregulation of a tumor suppressor can result in decreased levels of tumor suppressor protein in the cell. As another example, a dysregulation of the expression or activity or level of a non-kinase gene, non-kinase protein, or any of these may be a mutation in a non-kinase gene encoding a gene that is constitutively active or compared to a non-kinase gene that does not include the The non-kinase protein encoded by the mutated non-kinase gene is a non-kinase protein with increased activity. As another example, a dysregulation of the expression or activity or level of a non-kinase gene, non-kinase protein, or any of these may be a mutation in a non-kinase gene encoding a gene that is constitutively active or compared to a non-kinase gene that does not include the The non-kinase protein encoded by the mutated non-kinase gene is a non-kinase protein with increased activity. For example, dysregulation of the expression or activity or level of a non-kinase gene, a non-kinase protein, or either may be the result of a gene or chromosomal translocation that results in the expression of a fusion protein comprising The first part of the non-kinase protein and the second part of the partner protein (ie, not the main protein). In some instances, dysregulation of the expression or activity or level of a non-kinase gene, non-kinase protein, or either may be the result of a genetic translocation of one non-kinase gene with a different gene. In some such embodiments, the non-kinase can be selected from the group consisting of aromatase, BRCA2, CDK2NB, CDKN2A, EHMT2, GNAS, MDM2, Myc, NF1, RAS (eg, KRAS), and SOS1.

Multiple kinase inhibitors (MKI) or target-specific inhibitors (eg, BRAF inhibitors, EGFR inhibitors, MEK inhibitors, ALK inhibitors, ROS1 inhibitors, MET inhibitors, aromatase inhibitors, RAF inhibitors, or RAS inhibitors) Inhibitors) treatment of cancer patients may cause RET gene, RET kinase or its expression or activity or level of disorders, and/or resistance to RET inhibitors. See, eg, Bhinge et al., Oncotarget 8:27155-27165, 2017; Chang et al., Yonsei Med. J. 58:9-18, 2017; and Lopez-Delisle et al., doi: 10.1038/s41388-017-0039-5 , Oncogene 2018.

Use RET inhibitors with multiple kinase inhibitors or target-specific inhibitors (eg, BRAF inhibitors, EGFR inhibitors, MEK inhibitors, ALK inhibitors, ROS1 inhibitors, MET inhibitors, aromatase inhibitors, RAF inhibitors, or Combination treatment of RAS inhibitors) in cancer patients may have increased therapeutic efficacy compared to treatment of the same or similar patients with RET inhibitors as monotherapy or multiple kinase inhibitors or target-specific inhibitors as monotherapy. See eg Tang et al., doi: 10.1038/modpathol.2017.109, Mod. Pathol. 2017; Andreucci et al., Oncotarget 7:80543-80553, 2017; Nelson-Taylor et al., Mol. Cancer Ther. 16:1623-1633, 2017; and Kato et al., Clin. Cancer Res. 23:1988-1997, 2017.

Provided herein are methods for treating a patient with a cancer, such as any of the cancers described herein, who have previously been administered a multiple kinase inhibitor (MKI) or a target-specific inhibitor (e.g., a BRAF inhibitor, an EGFR inhibitor , MEK inhibitor, ALK inhibitor, ROS1 inhibitor, MET inhibitor, aromatase inhibitor, RAF inhibitor, or RAS inhibitor) (for example in the form of a monotherapy), comprising: administering to the patient ( i) a therapeutically effective dose of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof in monotherapy, or (ii) a therapeutically effective dose of a compound of formula I or a pharmaceutically acceptable salt or solvent thereof A compound and a therapeutically effective dose of a previously administered MKI or a previously administered target-specific inhibitor.

Provided herein are methods for treating previously administered MKI or target-specific inhibitors (e.g., BRAF inhibitors, EGFR inhibitors, MEK inhibitors, ALK inhibitors, ROS1 inhibitors, MET inhibitors, aromatase inhibitors, RAF inhibitors). or RAS inhibitor) (e.g., in the form of monotherapy) in a patient with cancer, such as any of the cancers described herein, comprising: identifying a patient with a RET gene, RET kinase, or expression or activity thereof or levels of dysregulated cancer cells; and administering to identified patients (i) a therapeutically effective dose of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof in monotherapy, or (ii) treating An effective dose of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective dose of a previously administered MKI or a previously administered target-specific inhibitor.

Provided herein are methods for treating a patient with cancer, such as any of the cancers described herein, comprising: administering to the patient a therapeutically effective amount of a MKI or a target-specific inhibitor, such as BRAF inhibitors, EGFR inhibitors, MEK inhibitors, ALK inhibitors, ROS1 inhibitors, MET inhibitors, aromatase inhibitors, RAF inhibitors, or RAS inhibitors) (eg, as monotherapy); after this period , identifying patients with cancer cells that contain a disorder of the RET gene, RET kinase, or expression or activity or level thereof; and administering to the identified patient (i) a therapeutically effective dose of a compound of formula I in monotherapy or its pharmaceutical or (ii) a therapeutically effective dose of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective dose of previously administered MKI or previously administered with target-specific inhibitors.

Provided herein are methods for treating a patient with a cancer (such as any of the cancers described herein) having a dysregulation of the BRAF gene, BRAF kinase, or expression or activity or level thereof comprising administering to the patient (i) A therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, and (ii) a therapeutically effective amount of a BRAF inhibitor (such as one of the BRAF inhibitors described herein or known in the art) either).

Provided herein are methods for treating a patient with cancer, such as any of the cancers described herein, comprising: identifying in the patient a cancer cell comprising a dysregulation of the BRAF gene, BRAF kinase, or expression or activity or amount thereof; and administering (i) a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, and (ii) a therapeutically effective amount of a BRAF inhibitor (such as described herein or any of the BRAF inhibitors known in the art).

Provided herein are methods for treating a patient with a cancer (such as any of the cancers described herein) having a dysregulation of the EGFR gene, EGFR protein, or expression or activity or level thereof, comprising administering to the patient (i) A therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, and (ii) a therapeutically effective amount of an EGFR inhibitor (such as one of the EGFR inhibitors described herein or known in the art) either).

Provided herein are methods for treating a patient with cancer, such as any of the cancers described herein, comprising: identifying in the patient a cancer cell comprising a dysregulation of the EGFR gene, EGFR protein, or expression or activity or amount thereof; and administering (i) a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, and (ii) a therapeutically effective amount of an EGFR inhibitor (such as described herein or any of the EGFR inhibitors known in the art).

Provided herein are methods for treating a patient with a cancer (such as any of the cancers described herein) having a dysregulation of a MEK gene, protein, or expression or activity or level thereof, comprising administering to the patient (i) a treatment An effective amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, and (ii) a therapeutically effective amount of a MEK inhibitor (such as one of the MEK inhibitors described herein or known in the art) either).

Provided herein are methods for treating a patient with cancer, such as any of those described herein, comprising: identifying a patient with a disorder comprising a MEK gene, MEK protein, or expression or activity or amount thereof and administering (i) a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, and (ii) a therapeutically effective amount of a MEK inhibitor (such as herein any of the MEK inhibitors described in or known in the art).

Provided herein are methods for treating a patient with a cancer (such as any of the cancers described herein) having a dysregulation of the ALK gene, ALK protein, or expression or activity or level thereof, comprising administering to the patient (i) A therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, and (ii) a therapeutically effective amount of an ALK inhibitor (such as one of the ALK inhibitors described herein or known in the art) either).

Provided herein are methods for treating a patient with cancer, such as any of the cancers described herein, comprising: identifying in the patient a cancer cell comprising a dysregulation of the ALK gene, ALK protein, or expression or activity or amount thereof; and administering (i) a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, and (ii) a therapeutically effective amount of an ALK inhibitor (such as described herein or any of the ALK inhibitors known in the art).

Provided herein are methods for treating a patient with a cancer (eg, any of the cancers described herein) having a ROS gene, ROS protein, or expression or activity or level thereof, comprising administering to the patient (i) a therapeutically effective An amount of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, and (ii) a therapeutically effective amount of a ROS inhibitor (such as any of the ROS inhibitors described herein or known in the art) one).

Provided herein are methods for treating a patient with cancer, such as any of the cancers described herein, comprising: identifying in the patient a cancer cell comprising a dysregulation of a ROS gene, ROS protein, or expression or activity or amount thereof; and administering (i) a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, and (ii) a therapeutically effective amount of a ROS inhibitor (such as described herein or any of the ROS inhibitors known in the art).

Provided herein are methods for treating a patient with a cancer (such as any of the cancers described herein) having a dysregulation of the MET gene, MET protein, or expression or activity or level thereof, comprising administering to the patient (i) A therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, and (ii) a therapeutically effective amount of a MET inhibitor (such as among the MET inhibitors described herein or known in the art) either).

Provided herein are methods for treating a patient with cancer, such as any of the cancers described herein, comprising: identifying in the patient a cancer cell comprising a dysregulation of the MET gene, MET protein, or expression or activity or amount thereof; and administering (i) a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, and (ii) a therapeutically effective amount of a MET inhibitor (such as described herein or any of the MET inhibitors known in the art).

Provided herein are methods for treating a patient with a cancer (such as any of the cancers described herein) having a dysregulation of the aromatase gene, aromatase protein, or expression or activity or level thereof, comprising administering to the patient ( i) a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, and (ii) a therapeutically effective amount of an aromatase inhibitor (such as an aromatase described herein or known in the art) any of the enzyme inhibitors).

Provided herein are methods for treating a patient with cancer, such as any of the cancers described herein, comprising: identifying a patient with a cancer comprising a disorder of the aromatase gene, aromatase protein, or expression or activity or amount thereof cells; and administering (i) a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, and (ii) a therapeutically effective amount of an aromatase inhibitor (such as herein any of the aromatase inhibitors described or known in the art).

Provided herein are methods for treating a patient with a cancer, such as any of the cancers described herein, having a dysregulation of the RAF gene, RAF protein, or expression or activity or level thereof, comprising administering to the patient (i) A therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, and (ii) a therapeutically effective amount of a RAF inhibitor (such as one of the RAF inhibitors described herein or known in the art) either).

Provided herein are methods for treating a patient with cancer, such as any of the cancers described herein, comprising: identifying in the patient a cancer cell comprising a dysregulation of the RAF gene, RAF protein, or expression or activity or amount thereof; and administering (i) a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, and (ii) a therapeutically effective amount of a RAF inhibitor (such as described herein or any of the RAF inhibitors known in the art).

Provided herein are methods for treating a patient with a cancer, such as any of the cancers described herein, having a dysregulation of a RAS gene, RAS protein, or expression or activity or level thereof, comprising administering to the patient (i) A therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, and (ii) a therapeutically effective amount of a RAS inhibitor (such as one of the RAS inhibitors described herein or known in the art) either).

Provided herein are methods for treating a patient with cancer, such as any of the cancers described herein, comprising: identifying in the patient a cancer cell comprising a dysregulation of a RAS gene, RAS protein, or expression or activity or amount thereof; and administering (i) a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, and (ii) a therapeutically effective amount of a RAS inhibitor (such as described herein or any of the RAS inhibitors known in the art).

The phrase "dysregulation of the expression or activity or content of BRAF gene, BRAF protein, or any of them" refers to a genetic mutation (such as a chromosomal translocation that causes expression of a fusion protein comprising a BRAF kinase domain and a fusion partner, causing BRAF gene mutations causing expression of BRAF protein with one amino acid deletion (compared to wild-type BRAF protein), BRAF gene mutations causing expression of BRAF protein with one or more point mutations (compared to wild-type BRAF protein) , a mutation in the BRAF gene that causes expression of a BRAF protein with at least one inserted amino acid (compared to wild-type BRAF protein), a gene duplication that causes an increase in the amount of BRAF protein in a cell, or a gene that causes an increase in the amount of BRAF protein in a cell mutations in regulatory sequences (such as promoters and/or enhancers), alternatively spliced forms of BRAF mRNA that produce BRAF proteins with deletions of at least one amino acid in the BRAF protein (compared to wild-type BRAF protein), or by abnormal Dysregulation of cell signaling and/or autocrine/paracrine signaling results in increased expression (eg, increased levels) of wild-type BRAF kinase in mammalian cells (eg, compared to control non-cancerous cells). As another example, a dysregulation of the expression or activity or level of a BRAF gene, BRAF protein, or either may be a mutation in the BRAF gene encoding a BRAF protein that is constitutively active or that is compared with The protein encoded by the BRAF gene has increased activity. For example, dysregulation of the expression or activity or content of the BRAF gene, BRAF protein, or any of them may be the result of a gene or chromosomal translocation that results in the expression of a fusion protein that includes functional The first part of the BRAF protein and the second part of the partner protein (ie, not BRAF) of the sex kinase domain. In some instances, dysregulation of the expression or activity or level of a BRAF gene, BRAF protein, or either can be the result of a genetic translocation of one BRAF gene with another non-BRAF gene.

Non-limiting examples of BRAF inhibitors include dabrafenib, vemurafenib (also known as RG7204 or PLX4032), sorafenib tosylate, PLX-4720, GDC -0879, BMS-908662 (Bristol-Meyers Squibb), LGX818 (Novartis), PLX3603 (Hofmann-LaRoche), RAF265 (Novartis), RO5185426 (Hofmann-LaRoche), and GSK2118436 (GlaxoSmithKline). Other examples of BRAF inhibitors are known in the art.

The phrase "disregulation of the expression or activity or content of EGFR gene, EGFR protein, or any of them" refers to gene mutations (such as chromosomal translocations that cause expression of fusion proteins that include EGFR kinase domains and fusion partners, that include at least EGFR gene mutations causing expression of EGFR protein with one amino acid deletion (compared to wild-type EGFR protein), EGFR gene mutations causing expression of EGFR protein with one or more point mutations (compared to wild-type EGFR protein) , a mutation in the EGFR gene that causes the expression of an EGFR protein with at least one inserted amino acid (compared to the wild-type EGFR protein), a gene duplication that causes an increase in the amount of the EGFR protein in the cell, or a gene that causes an increase in the amount of the EGFR protein in the cell regulatory sequence (eg, promoter and/or enhancer) mutations), alternative spliced forms of EGFR mRNA that produce an EGFR protein that has at least one amino acid missing in the EGFR protein (compared to wild-type EGFR protein), or caused by an abnormal Increased expression (eg, increased levels) of wild-type EGFR protein in mammalian cells caused by dysregulation of cell signaling and/or autocrine/paracrine signaling (eg, compared to control non-cancerous cells). As another example, a dysregulation of the expression or activity or level of the EGFR gene, EGFR protein, or either may be a mutation in the EGFR gene encoding an EGFR gene that is constitutively active or compared to an EGFR gene that does not include the mutation. The protein encoded by the gene is an EGFR protein with increased activity. For example, dysregulation of the expression or activity or content of the EGFR gene, EGFR protein, or any of them may be the result of a gene or chromosomal translocation that results in the expression of a fusion protein comprising functional The sex kinase domain is the first part of the EGFR protein and the second part of the partner protein (ie, not EGFR). In some instances, dysregulation of the expression or activity or level of an EGFR gene, EGFR protein, or either may be the result of a genetic translocation of one EGFR gene with another non-EGFR gene. In some embodiments, the EGFR mutation is a T790M mutation. In some embodiments, the EGFR mutation is a C797S mutation.

Non-limiting examples of EGFR inhibitors include gefitinib, erlotinib, brigatinib, lapatinib, neratinib, icotinib, afatinib, dacomitinib, Poziotinib, Vandetanib, Afatinib, AZD9291, CO-1686, HM61713, AP26113, CI-1033, PKI-166, GW-2016, EKB-569, PDI-168393, AG- 1478. CGP-59326A. Other examples of EGFR inhibitors are known in the art.

The phrase "dysregulation of expression or activity or content of MEK gene, MEK protein, or any of them" refers to a genetic mutation (such as a chromosomal translocation that causes expression of a fusion protein comprising a MEK kinase domain and a fusion partner, causing MEK gene mutation causing expression of MEK protein with one amino acid deletion (compared to wild-type MEK protein), MEK gene mutation causing expression of MEK protein with one or more point mutations (compared to wild-type MEK protein) , a mutation in the MEK gene that causes expression of a MEK protein with at least one inserted amino acid (compared to wild-type MEK protein), a gene duplication that causes an increase in the amount of the MEK protein in the cell, or a gene duplication that causes an increase in the amount of the MEK protein in the cell regulatory sequence (such as promoter and/or enhancer) mutations), alternative splicing forms of MEK mRNA that produce MEK protein with at least one amino acid deletion in the MEK protein (compared to wild-type MEK protein), or caused by abnormal Dysregulation of cell signaling and/or autocrine/paracrine signaling results in increased expression (eg, increased levels) of wild-type MEK kinase in mammalian cells (eg, compared to control non-cancerous cells). As another example, a dysregulation of the expression or activity or level of a MEK gene, a MEK protein, or either may be a mutation in the MEK gene encoding a MEK protein that is constitutively active or that is compared to an expression resulting from the absence of the mutation. The protein encoded by the MEK gene has increased activity. For example, the MEK gene, MEK protein, or the expression or activity or content of any one of the disorder can be the result of gene or chromosomal translocation, the gene or chromosomal translocation causes the expression of fusion protein, the fusion protein contains including functional The first part of the MEK protein of the sex kinase domain and the second part of the partner protein (ie, not MEK). In some instances, dysregulation of the expression or activity or level of a MEK gene, MEK protein, or either may be the result of a genetic translocation of one MEK gene with another non-MEK gene.

Non-limiting examples of MEK inhibitors include mekinist, trametinib (GSK1120212), cobimetinib (XL518), binitinib (MEK162), Selumetinib, PD-325901, CI-1040, PD035901, TAK-733, PD098059, U0126, AS703026/MSC1935369, XL-518/GDC-0973, BAY869766/RDEA119 and GSK1120212. Other examples of MEK inhibitors are known in the art.

The phrase "disregulation of the expression or activity or content of ALK gene, ALK protein, or any of them" refers to gene mutations (such as chromosomal translocations that cause expression of fusion proteins that include ALK kinase domains and fusion partners, that include at least ALK gene mutations causing expression of ALK protein with one amino acid deletion (compared to wild-type ALK protein), ALK gene mutations causing expression of ALK protein with one or more point mutations (compared to wild-type ALK protein) , a mutation in the ALK gene that causes expression of an ALK protein with at least one inserted amino acid (compared to a wild-type ALK protein), a gene duplication that causes an increase in the content of the ALK protein in the cell, or a gene duplication that causes an increase in the content of the ALK protein in the cell regulatory sequence (such as promoter and/or enhancer) mutation), alternative splicing form of ALK mRNA that produces ALK protein with at least one amino acid deletion in ALK protein (compared to wild-type ALK protein), or caused by abnormal Increased expression (eg, increased level) of wild-type ALK protein in mammalian cells caused by dysregulation of cell signaling and/or autocrine/paracrine signaling (eg, compared to control non-cancerous cells). As another example, a dysregulation of the expression or activity or level of the ALK gene, ALK protein, or either may be a mutation in the ALK gene that encodes a gene that is constitutively active or compared to an ALK gene that does not include the mutation. The encoded protein is an ALK protein with increased activity. For example, the ALK gene, the ALK protein, or the expression or activity or content of any one of the disorder can be the result of gene or chromosomal translocation, the gene or chromosomal translocation causes the expression of fusion protein, the fusion protein contains including functional The first part of the ALK protein and the second part of the partner protein (ie, not ALK) of the sex kinase domain. In some instances, dysregulation of the expression or activity or level of the ALK gene, ALK protein, or either may be the result of a genetic translocation of one ALK gene with another non-ALK gene.

Non-limiting examples of ALK inhibitors include Xalkori, Zykadia, Alecensa, dalantercept, ACE-041 (Brigatinib ))(AP26113), entrectinib (NMS-E628), PF-06463922 (Pfizer), TSR-011 (Tesaro), CEP-37440 (Teva), CEP-37440 (Teva), X-396 (Xcovery) and ASP-3026 (Astellas). Other examples of ALK inhibitors are known in the art.

The phrase "disregulation of the expression or activity or content of ROS1 gene, ROS1 protein, or any of them" refers to gene mutations (such as chromosomal translocations that cause expression of fusion proteins that include ROS1 kinase domains and fusion partners, that include at least ROS1 gene mutations causing expression of ROS1 protein with one amino acid deletion (compared to wild-type ROS1 protein), ROS1 gene mutations causing expression of ROS1 protein with one or more point mutations (compared to wild-type ROS1 protein) , a mutation in the ROS1 gene that causes expression of a ROS1 protein with at least one inserted amino acid compared to a wild-type ROS1 protein, a gene duplication that causes an increase in the amount of the ROS1 protein in a cell, or a gene that causes an increase in the amount of the ROS1 protein in a cell regulatory sequence (such as promoter and/or enhancer) mutations), alternative spliced forms of ROS1 mRNA that produce ROS1 protein with at least one amino acid deletion in the ROS1 protein (compared to wild-type ROS1 protein), or caused by abnormal Increased expression (eg, increased level) of wild-type ROS1 protein in mammalian cells caused by dysregulation of cell signaling and/or autocrine/paracrine signaling (eg, compared to control non-cancerous cells). As another example, a dysregulation of the expression or activity or level of the ROS1 gene, the ROS1 protein, or any of them may be a mutation in the ROS1 gene encoding a ROS1 protein that is constitutively active or that is compared to the expression caused by not including the mutation. The protein encoded by the ROS1 gene has increased activity. For example, the ROS1 gene, the ROS1 protein or the expression or the activity of any one of these dysregulation can be the result of gene or chromosomal translocation, and this gene or chromosomal translocation causes the expression of fusion protein, and this fusion protein comprises function The first part of the ROS1 protein of the sex kinase domain and the second part of the partner protein (ie, not ROS1). In some examples, dysregulation of the expression or activity or level of a ROS1 gene, ROS1 protein, or either may be the result of a genetic translocation of one ROS1 gene with another non-ROS1 gene.

Non-limiting examples of ROS1 inhibitors include crizotinib, entrectinib (RXDX-101), lorlatinib (PF-06463922), certinib, TPX-0005, DS-605 and cabozantinib. Other examples of ROS1 inhibitors are known in the art.

The phrase "disregulation of expression or activity or content of MET gene, MET protein, or any of them" refers to a genetic mutation (such as a chromosomal translocation that causes expression of a fusion protein comprising a MET kinase domain and a fusion partner, causing MET gene mutations that cause expression of MET proteins with one amino acid deletion (compared to wild-type MET protein), MET gene mutations that cause expression of MET proteins with one or more point mutations (compared to wild-type MET protein) , a mutation in the MET gene that causes expression of a MET protein with at least one inserted amino acid (compared to a wild-type MET protein), a gene duplication that causes an increase in the amount of the MET protein in a cell, or a gene that causes an increase in the amount of the MET protein in a cell regulatory sequence (such as promoter and/or enhancer) mutation), alternative splicing form of MET mRNA that produces a MET protein with at least one amino acid deletion in the MET protein (compared to wild-type MET protein), or caused by abnormal Increased expression (eg, increased levels) of wild-type MET protein in mammalian cells caused by dysregulation of cell signaling and/or autocrine/paracrine signaling (eg, compared to control non-cancerous cells). As another example, a dysregulation of the expression or activity or level of the MET gene, the MET protein, or any of them may be a mutation in the MET gene encoding a MET protein that is constitutively active or compared to the expression or activity of the MET protein that does not include the mutation. The protein encoded by the MET gene has increased activity. For example, dysregulation of the expression or activity or content of the MET gene, the MET protein, or any of them may be the result of a gene or chromosomal translocation that results in the expression of a fusion protein comprising functional The first part of the MET protein of the sex kinase domain and the second part of the partner protein (ie, not MET). In some instances, dysregulation of the expression or activity or level of a MET gene, MET protein, or either may be the result of a genetic translocation of one MET gene with another non-MET gene.

Non-limiting examples of MET inhibitors include crizotinib, cabozantinib, JNJ-38877605, PF-04217903 (Pfizer), MK-2461, GSK 1363089, AMG 458 (Amgen), tivatinib, INCB28060 (Incyte ), PF-02341066 (Pfizer), E7050 (Eisai), BMS-777607 (Bristol-Meyers Squibb), JNJ-38877605 (Johnson & Johnson), ARQ197 (ArQule), GSK/1363089/XL880 (GSK/Exeilixis) and XL174 (BMS/Exelixis). Other examples of MET inhibitors are known in the art.

The phrase "dysregulation of the expression or activity or level of an aromatase gene, an aromatase protein, or either" refers to a genetic mutation (e.g. causing an aromatase comprising at least one amino acid deletion compared to a wild-type aromatase protein). Mutations in the aromatase gene for expression of the enzyme protein, mutations in the aromatase gene that cause expression of an aromatase protein with one or more point mutations (compared to the wild-type aromatase protein), mutations in the aromatase gene that cause expression of an aromatase protein with at least one inserted amino acid (compared to Aromatase gene mutations in the expression of aromatase protein compared to wild-type aromatase protein), gene duplications that result in increased levels of aromatase protein in cells, or regulatory sequences that cause increased levels of aromatase protein in cells (such as promoter and/or enhancer) mutations), alternative splicing forms of aromatase mRNA that produce an aromatase protein having at least one amino acid deletion in the aromatase protein (compared to the wild-type aromatase protein), or caused by abnormal cell signaling Increased expression (eg, increased levels) of wild-type aromatase in mammalian cells caused by transduction and/or autocrine/paracrine signaling dysregulation (eg, compared to control non-cancerous cells). As another example, a dysregulation of the expression or activity or level of an aromatase gene, an aromatase protein, or either can be a mutation in an aromatase gene encoding an aromatase gene that is constitutively active or compared to an aromatase gene that does not include the The protein encoded by the mutated aromatase gene is an aromatase protein with increased activity.

Non-limiting examples of aromatase inhibitors include Arimidex (anastrozole), Aromasin (exemestane), Femara (letrole azole (letrozole), Teslac (testolactone), and formestane. Other examples of aromatase inhibitors are known in the art.

The phrase "disregulation of the expression or activity or content of the RAF gene, RAF protein, or any of them" refers to a genetic mutation (such as a chromosomal translocation that causes expression of a fusion protein comprising the RAF kinase domain and a fusion partner, causing RAF gene mutations causing expression of RAF protein with one amino acid deletion (compared to wild-type RAF protein), RAF gene mutations causing expression of RAF protein with one or more point mutations (compared to wild-type RAF protein) , a mutation in the RAF gene that causes expression of a RAF protein with at least one inserted amino acid (compared to wild-type RAF protein), a gene duplication that causes an increase in the amount of RAF protein in a cell, or a gene that causes an increase in the amount of RAF protein in a cell regulatory sequence (such as promoter and/or enhancer) mutations), alternative spliced forms of RAF mRNA that produce RAF protein with at least one amino acid deletion in the RAF protein (compared to wild-type RAF protein), or caused by abnormal Increased expression (eg, increased levels) of wild-type RAF protein in mammalian cells caused by dysregulation of cell signaling and/or autocrine/paracrine signaling (eg, compared to control non-cancerous cells). As another example, a dysregulation of the expression or activity or level of a RAF gene, RAF protein, or either may be a mutation in the RAF gene encoding a RAF protein that is constitutively active or that is compared with The protein encoded by the RAF gene has increased activity. For example, a dysregulation of the expression or activity or content of the RAF gene, RAF protein, or any of them may be the result of a gene or chromosomal translocation that results in the expression of a fusion protein comprising functional The first part of the RAF protein and the second part of the partner protein (ie, not RAF) of the sex kinase domain. In some instances, dysregulation of the expression or activity or level of a RAF gene, RAF protein, or either may be the result of a genetic translocation of one RAF gene with another non-RAF gene.

Non-limiting examples of RAF inhibitors include sorafenib, vemurafenib, dabrafenib, BMS-908662/XL281, GSK2118436, RAF265, RO5126766 and RO4987655. Other examples of RAF inhibitors are known in the art.

The phrase "disregulation of the expression or activity or content of a RAS gene, a RAS protein, or any of them" refers to a genetic mutation (such as a chromosomal translocation that causes expression of a fusion protein comprising a RAS kinase domain and a fusion partner, causing RAS gene mutations causing expression of RAS proteins with one amino acid deletion (compared to wild-type RAS protein), RAS gene mutations causing expression of RAS proteins with one or more point mutations (compared to wild-type RAS protein) , a mutation in the RAS gene that causes expression of a RAS protein with at least one inserted amino acid (compared to a wild-type RAS protein), a gene duplication that causes an increase in the amount of the RAS protein in the cell, or a gene that causes an increase in the amount of the RAS protein in the cell regulatory sequence (eg, promoter and/or enhancer) mutations), alternative spliced forms of RAS mRNA that produce a RAS protein with at least one amino acid deletion in the RAS protein (compared to wild-type RAS protein), or caused by an abnormal Increased expression (eg, increased levels) of wild-type RAS protein in mammalian cells caused by dysregulation of cell signaling and/or autocrine/paracrine signaling (eg, compared to control non-cancerous cells). As another example, a dysregulation of the expression or activity or level of a RAS gene, a RAS protein, or either may be a mutation in the RAS gene encoding a RAS protein that is constitutively active or that is compared to the expression or activity resulting from the absence of the mutation. The protein encoded by the RAS gene has increased activity. For example, dysregulation of the expression or activity or content of the RAS gene, the RAS protein, or any of them may be the result of a gene or chromosomal translocation that results in the expression of a fusion protein comprising functional The first part of the RAS protein of the sex kinase domain and the second part of the partner protein (ie, not RAS). In some instances, dysregulation of the expression or activity or level of a RAS gene, RAS protein, or either may be the result of a genetic translocation of one RAS gene with another non-RAS gene.

Non-limiting examples of RAS inhibitors include Kobe0065 and Kobe2602. Other examples of RAS inhibitors are known in the art.

Non-limiting examples of multiple kinase inhibitors (MKIs) include dasatinib and sunitinib.

In some embodiments, provided herein are methods for treating an individual with cancer comprising: (a) administering to the individual one or more doses of a first RET inhibitor or a compound of Formula I or its pharmaceutical acceptable salt or solvate for a period of time; (b) after (a), determining whether the cancer cells in a sample obtained from the individual have at least one of the gene, protein, or expression or activity or content of either Dysregulation, wherein the gene or protein is selected from the group consisting of EGFR, MET, ALK, ROS1, KRAS, BRAF, RAS, PIK3CA, and HER2; and (c) 1) as monotherapy or in combination with another anticancer agent 2) administering an additional dose of the first RET inhibitor or a compound of formula I or a pharmaceutically acceptable salt or solvate thereof and an inhibitor of a targeted gene or protein (such as EGFR, MET, ALK, ROS1, KRAS, BRAF, RAS, PIK3CA, and HER2 inhibitors), or 3) if the individual has cancer cells that contain at least one dysregulation of a gene, protein, or expression or activity or content thereof, then Administration of the RET inhibitor of step a) is discontinued and the individual is administered an inhibitor of a targeted gene or protein (e.g., an inhibitor of EGFR, MET, ALK, ROS1, KRAS, BRAF, RAS, PIK3CA, and HER2), wherein the gene or the protein is selected from the group consisting of EGFR, MET, ALK, ROS1, KRAS, BRAF, RAS, PIK3CA, and HER2; or (d) reintroduced to the individual if the individual has cancer cells that do not contain a RET inhibitor resistance mutation An additional dose of the first RET inhibitor of step (a) is administered. In some embodiments, one or more disorders of gene, protein or expression or activity or content of any of them endow cancer cells or tumors with increased response to the first RET inhibitor or compound of formula I or pharmaceutically acceptable Resistance to treatment with a salt or solvate of the gene or protein selected from the group consisting of EGFR, MET, ALK, ROS1, KRAS, BRAF, RAS, PIK3CA and HER2. In some embodiments, the tumor is an NSCLC tumor and one or more of the genes, proteins, or one or more dysregulations in the expression or activity or level of any of them is selected from targetable mutations in EGFR or MET, targetable mutations involving ALK or ROS1 Rearrangements, or activating mutations in KRAS. In some embodiments, the tumor is a thyroid (non-MTC) tumor and the gene, protein, or one or more dysregulation of the expression or activity or level of any is selected from a targetable mutation in BRAF or an activating mutation in RAS. In some embodiments, the tumor is an MTC tumor and one or more dysregulation of the expression or activity or level of a gene, protein, or any of them is selected from a targetable mutation in ALK or an activating mutation in RAS. In some embodiments, the tumor is a pancreatic tumor and the dysregulation of one or more of the gene, protein, or expression or activity or level of any of these is an activating mutation in KRAS. In some embodiments, the tumor is a colorectal tumor and one or more dysregulation of the expression or activity or level of a gene, protein, or any of them is selected from a targetable mutation in BRAF or PIK3CA or an activating mutation in RAS. In some embodiments, the tumor is a breast tumor and the gene, protein, or one or more dysregulation of the expression or activity or level of any is selected from a targetable mutation in PIK3CA or a change in HER2.

Also provided are methods of selecting a therapy for an individual having cancer comprising: (a) administering to the individual one or more doses of a first RET inhibitor for a period of time; (b) after (a), determining Whether the cancer cells in the sample obtained from the individual have at least one RET inhibitor resistance mutation; and (c) if the individual has cancer cells that contain one or more RET inhibitor resistance mutations, the choice of monotherapy or in combination with another A compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, in combination with an anticancer agent is administered to an individual; or (d) if the individual has cancer cells that do not contain a RET inhibitor resistance mutation, an alternative dose is selected The first RET inhibitor of step (a) is administered to the individual. In some embodiments, when other doses of the first RET inhibitor of step (a) are selected for the individual, the method may further comprise selecting a dose of another anticancer agent for the individual. In some embodiments, one or more RET inhibitor resistance mutations confer increased resistance to cancer cell or tumor to treatment with a first RET inhibitor. In some embodiments, the one or more RET inhibitor resistance mutations include one or more RET inhibitor resistance mutations listed in Tables 3 and 4. For example, one or more RET inhibitor resistance mutations can include a substitution at amino acid position 804, such as V804M, V804L, or V804E, or a substitution at amino acid position 810, such as G810S, G810R, G810C, G810A, G810V and G810D. In some embodiments, the other anticancer agent is any anticancer agent known in the art. For example, the additional anticancer agent can be another RET inhibitor (eg, a second RET inhibitor). In some embodiments, the other anticancer agent may be immunotherapy. In some embodiments of step (c), the second RET inhibitor can be the first RET inhibitor administered in step (a).

Also provided are methods for treating an individual with cancer, comprising: (a) determining a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, that has been previously administered one or more doses from a patient with cancer. whether the cancer cells in the sample obtained from the subject of the drug have one or more RET inhibitor resistance mutations; Administration of a second RET inhibitor or a second compound of Formula I or a pharmaceutically acceptable salt or solvate thereof to an individual with cancer cells; or (c) readministration to an individual with a resistance mutation that does not contain a RET inhibitor with an additional dose of a previously administered compound of formula I, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, when an additional dose of the compound of formula I of step (a) or a pharmaceutically acceptable salt or solvate thereof is administered to the individual, another anticancer agent may also be administered to the individual. In some embodiments, one or more RET inhibitor resistance mutations confer increased resistance to treatment with a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, in the cancer cell or tumor. In some embodiments, the other anticancer agent is any anticancer agent known in the art. For example, the additional anticancer agent can be another RET inhibitor (eg, a second RET inhibitor). In some embodiments, the other anticancer agent may be immunotherapy. In some embodiments, the other RET inhibitor may be the compound of formula I administered in step (a), or a pharmaceutically acceptable salt or solvate thereof.

Also provided are methods of selecting a therapy for an individual having cancer comprising: (a) administering to the individual one or more doses of a first RET inhibitor for a period of time; (b) after (a), determining Whether the cancer cells in the sample obtained from the individual have at least one RET inhibitor resistance mutation; and (c) if the individual has cancer cells that contain one or more RET inhibitor resistance mutations, the choice of monotherapy or in combination with another A second RET inhibitor in the form of an anticancer agent combination; or (d) if the individual has cancer cells that do not contain a RET inhibitor resistance mutation, an additional dose of the first RET inhibitor of step (a) is selected for use in the individual . In some embodiments, when other doses of the first RET inhibitor of step (a) are selected for the individual, the method may further comprise selecting a dose of another anticancer agent for the individual. In some embodiments, one or more RET inhibitor resistance mutations confer increased resistance to cancer cell or tumor to treatment with a first RET inhibitor. In some embodiments, the one or more RET inhibitor resistance mutations include one or more RET inhibitor resistance mutations listed in Tables 3 and 4. For example, one or more RET inhibitor resistance mutations can include a substitution at amino acid position 804, such as V804M, V804L, or V804E, or a substitution at amino acid position 810, such as G810S, G810R, G810C, G810A, G810V and G810D. In some embodiments, the other anticancer agent is any anticancer agent known in the art. For example, the other anticancer agent is another RET inhibitor (such as a compound of formula I or a pharmaceutically acceptable salt or solvate thereof). In some embodiments, the other anticancer agent is immunotherapy. In some embodiments, another RET inhibitor may be the first RET inhibitor administered in step (a).

Also provided are methods of selecting therapy for an individual with cancer comprising: (a) determining the cancer in a sample obtained from an individual with cancer who has previously been administered one or more doses of a first RET inhibitor whether the cells have one or more RET inhibitor resistance mutations; (b) if the individual has cancer cells containing at least one RET inhibitor resistance mutation, formula I is selected as monotherapy or in combination with another anticancer agent The compound or a pharmaceutically acceptable salt or solvate thereof is administered to an individual; or (c) if the individual has cancer cells that do not contain a RET inhibitor resistance mutation, an alternative dose of the first a RET inhibitor. In some embodiments, when selecting other doses of the first RET inhibitor previously administered to the individual for the individual, the method may further comprise selecting another anticancer agent (e.g., a compound of formula I or a pharmaceutically acceptable Accepted salt or solvate or immunotherapy) doses are used for the individual. In some embodiments, one or more RET inhibitor resistance mutations confer increased resistance to cancer cell or tumor to treatment with a first RET inhibitor. In some embodiments, the one or more RET inhibitor resistance mutations include one or more RET inhibitor resistance mutations listed in Tables 3 and 4. For example, one or more RET inhibitor resistance mutations can include a substitution at amino acid position 804, such as V804M, V804L, or V804E, or a substitution at amino acid position 810, such as G810S, G810R, G810C, G810A, G810V and G810D. In some embodiments, the other anticancer agent is any anticancer agent known in the art. For example, the additional anticancer agent can be another RET inhibitor (eg, a second RET inhibitor). In some embodiments, the other anticancer agent may be immunotherapy. In some embodiments of step (c), the second RET inhibitor can be the first RET inhibitor administered in step (a).

Also provided are methods of selecting treatment for an individual with cancer comprising: (a) determining the cancer in a sample obtained from an individual with cancer who has previously been administered one or more doses of a first RET inhibitor whether the cells have one or more RET inhibitor resistance mutations; (b) if the individual has cancer cells with at least one RET inhibitor resistance mutation, select a second anticancer agent as monotherapy or in combination with another anticancer agent A RET inhibitor is administered to the individual; or (c) if the individual has cancer cells that do not contain a RET inhibitor resistance mutation, an additional dose of the first RET inhibitor that has been previously administered to the individual is selected. In some embodiments, when selecting other doses of the first RET inhibitor previously administered to the individual for the individual, the method may further comprise selecting another anticancer agent (e.g., a compound of formula I or a pharmaceutically acceptable salt or solvate, or immunotherapy) for the individual. In some embodiments, one or more RET inhibitor resistance mutations confer increased resistance to cancer cell or tumor to treatment with a first RET inhibitor. In some embodiments, the one or more RET inhibitor resistance mutations include one or more RET inhibitor resistance mutations listed in Tables 3 and 4. For example, one or more RET inhibitor resistance mutations can include a substitution at amino acid position 804, such as V804M, V804L, or V804E, or a substitution at amino acid position 810, such as G810S, G810R, G810C, G810A, G810V and G810D. In some embodiments, the other anticancer agent is any anticancer agent known in the art. For example, the other anticancer agent can be another RET inhibitor (eg, a compound of formula I or a pharmaceutically acceptable salt or solvate thereof). In some embodiments, the other anticancer agent may be immunotherapy. In some embodiments, another RET inhibitor may be the first RET inhibitor administered in step (a).

Also provided are methods of determining an individual's risk of developing a cancer that has some resistance to a first RET inhibitor, comprising: determining whether cells in a sample obtained from the individual have one or more RET inhibitor resistance mutations; Individuals with cells of one or more RET inhibitor resistance mutations have an increased likelihood of developing a cancer that has some resistance to the first RET inhibitor. Also provided are methods of determining an individual's risk of developing a cancer that has some resistance to a first RET inhibitor, comprising: identifying an individual with cells containing one or more RET inhibitor resistance mutations that has an increased occurrence of a first RET inhibitor The possibility of some cancers being resistant to the drug. Also provided are methods of determining the presence of a cancer having some resistance to a first RET inhibitor comprising: determining whether cancer cells in a sample obtained from an individual have one or more RET inhibitor resistance mutations; An individual having cancer cells with one or more RET inhibitor resistance mutations has a cancer that has some resistance to a first RET inhibitor. Also provided is a method of determining the presence in an individual of a cancer that has some resistance to a first RET inhibitor comprising: determining that an individual with cancer cells containing one or more RET inhibitor resistance mutations has a cancer that is resistant to a first RET inhibitor Some resistant cancers. In some embodiments, one or more RET inhibitor resistance mutations confer increased resistance to cancer cell or tumor to treatment with a first RET inhibitor. In some embodiments, the one or more RET inhibitor resistance mutations include one or more RET inhibitor resistance mutations listed in Tables 3 and 4. For example, one or more RET inhibitor resistance mutations can include a substitution at amino acid position 804, such as V804M, V804L, or V804E, or a substitution at amino acid position 810, such as G810S, G810R, G810C, G810A, G810V and G810D.

In some embodiments of any of the methods described herein, the RET inhibitor resistance mutation that confers increased resistance to cancer cell or tumor to treatment with a first RET inhibitor may be Table 3 or Any of the RET inhibitor resistance mutations listed in 4 (e.g., a substitution at amino acid position 804, such as V804M, V804L, or V804E, or a substitution at amino acid position 810, such as G810S, G810R, G810C , G810A, G810V and G810D).

In some embodiments, the presence of one or more RET inhibitor resistance mutations in the tumor renders the tumor more resistant to treatment with a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof. The following describes methods applicable when a RET inhibitor resistance mutation renders the tumor more resistant to treatment with a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof. For example, provided herein are methods for treating an individual with cancer comprising: identifying an individual having cancer cells that contain one or more RET inhibitor resistance mutations; and administering to the identified individual as a monotherapy Treatment with a compound of formula I or a pharmaceutically acceptable salt or solvate thereof (eg a second RET kinase inhibitor) is not included. Also provided are methods for treating an individual identified as having cancer cells containing one or more RET inhibitor resistance mutations comprising administering to the individual as monotherapy excluding a compound of formula I or a pharmaceutically acceptable salt thereof or solvated treatment (eg a second RET kinase inhibitor). In some embodiments, one or more RET inhibitor resistance mutations confer increased resistance to treatment with a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, in the cancer cell or tumor.

Also provided are methods of selecting for treatment of an individual with cancer comprising: identifying the individual as having cancer cells containing one or more RET inhibitor resistance mutations; and selecting to exclude a compound of formula I or a pharmaceutical thereof as a monotherapy Treatment with a pharmaceutically acceptable salt or solvate (eg, a second RET kinase inhibitor) is used in the identified individual. Also provided are methods of selecting treatment for an individual with cancer comprising: selecting a treatment that excludes a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, as a monotherapy (e.g., a second RET kinase Inhibitors) are used to identify individuals with cancer cells containing one or more RET inhibitor resistance mutations. Also provided is a method of selecting an individual with cancer for treatment that does not include a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, as a monotherapy, such as a second RET kinase inhibitor, comprising: identifying The individual has cancer cells that contain one or more RET inhibitor resistance mutations; and the identified individual is selected for treatment that does not include a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as a monotherapy (e.g. second RET kinase inhibitor). Also provided is a method of selecting an individual with cancer for treatment that does not include a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, as a monotherapy, such as a second RET kinase inhibitor, comprising: selecting Individuals identified as having cancer cells containing one or more RET inhibitor resistance mutations are treated without a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, as monotherapy. In some embodiments, one or more RET inhibitor resistance mutations confer increased resistance to treatment with a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, in the cancer cell or tumor.

Also provided is a method of determining the likelihood that an individual with cancer will respond positively to treatment with a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, as a monotherapy, comprising: determining from the individual Whether the cancer cells in the sample have one or more RET inhibitor resistance mutations; The likelihood of a positive response to treatment with the above acceptable salt or solvate is reduced. Also provided is a method of determining the likelihood that an individual with cancer will respond positively to treatment with a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, in monotherapy, comprising: determining the likelihood of an individual having cancer containing a Individuals with cancer cells having one or more RET inhibitor resistance mutations are less likely to respond positively to treatment with a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, as monotherapy. Also provided is a method of predicting the efficacy of treatment with a compound of formula I as a monotherapy, or a pharmaceutically acceptable salt or solvate thereof, in an individual suffering from cancer comprising: determining in a sample obtained from the individual Whether the cancer cell has one or more RET inhibitor resistance mutations; Individuals with cancer cells harboring one or more RET inhibitor resistance mutations are unlikely to be effective. Also provided is a method of predicting the efficacy of treatment with a compound of formula I as a monotherapy, or a pharmaceutically acceptable salt or solvate thereof, in an individual with cancer comprising: determining the efficacy of a compound of formula I as a monotherapy Treatment with a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, is unlikely to be effective in individuals with cancer cells containing one or more RET inhibitor resistance mutations in a sample obtained from the individual. In some embodiments, one or more RET inhibitor resistance mutations confer increased resistance to treatment with a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, in the cancer cell or tumor.

Also provided are methods for treating an individual with cancer comprising: (a) administering one or more doses of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, for a period of time; (b) After (a), determining whether cancer cells in a sample obtained from the individual have one or more RET inhibitor resistance mutations; and (c) administering to the individual having cancer cells that contain one or more RET inhibitor resistance mutations with a second RET inhibitor or a second compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, as monotherapy or in combination with another anticancer agent; Individuals with cancer cells with drug-resistant mutations are then administered an additional dose of the compound of formula I of step (a) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, another anti-cancer agent or The second compound of formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, one or more RET inhibitor resistance mutations confer increased resistance to treatment with a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, in the cancer cell or tumor. In some embodiments, the other anticancer agent is any anticancer agent known in the art. For example, the additional anticancer agent can be another RET inhibitor (eg, a second RET inhibitor). In some embodiments, the other anticancer agent may be immunotherapy. In some embodiments, the other RET inhibitor may be the compound of formula I administered in step (a), or a pharmaceutically acceptable salt or solvate thereof.

Also provided are methods for treating an individual with cancer, comprising: (a) determining a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, that has been previously administered one or more doses from a patient with cancer. whether the cancer cells in the sample obtained from the subject of the drug have one or more RET inhibitor resistance mutations; Administration of a second RET inhibitor or a second compound of Formula I or a pharmaceutically acceptable salt or solvate thereof to an individual with cancer cells; or (c) readministration to an individual with a resistance mutation that does not contain a RET inhibitor with an additional dose of a previously administered compound of formula I, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, when an additional dose of the compound of formula I of step (a) or a pharmaceutically acceptable salt or solvate thereof is administered to the individual, another anticancer agent may also be administered to the individual. In some embodiments, one or more RET inhibitor resistance mutations confer increased resistance to treatment with a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, in the cancer cell or tumor. In some embodiments, the other anticancer agent is any anticancer agent known in the art. For example, the additional anticancer agent can be another RET inhibitor (eg, a second RET inhibitor). In some embodiments, the other anticancer agent may be immunotherapy. In some embodiments, the other RET inhibitor may be the compound of formula I administered in step (a), or a pharmaceutically acceptable salt or solvate thereof.

Also provided is a method of selecting for treatment of an individual with cancer comprising: (a) administering to the individual one or more doses of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, for a period of time (b) after (a), determining whether the cancer cells in a sample obtained from the individual have one or more RET inhibitor resistance mutations; and (c) if the individual has cancer cells containing a RET inhibitor resistance mutation, then a second RET inhibitor or a second compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, is selected for use in the individual as monotherapy or in combination with another anticancer agent; or (d) if the individual For cancer cells with RET inhibitor-resistant mutations, other doses of the compound of formula I in step (a) or a pharmaceutically acceptable salt or solvate thereof are selected for individual use. In some embodiments, when selecting other doses of the compound of formula I in step (a) or a pharmaceutically acceptable salt or solvate thereof for the individual, the method may also include further selecting another anticancer agent. In some embodiments, one or more RET inhibitor resistance mutations confer increased resistance to treatment with a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, in the cancer cell or tumor. In some embodiments, the other anticancer agent is any anticancer agent known in the art. For example, the additional anticancer agent can be another RET inhibitor (eg, a second RET inhibitor). In some embodiments, the other anticancer agent may be immunotherapy. In some embodiments, the other RET inhibitor may be the compound of formula I administered in step (a), or a pharmaceutically acceptable salt or solvate thereof.

Also provided are methods of selecting for treatment of an individual with cancer comprising: (a) determining a compound of formula I or a pharmaceutically acceptable salt thereof or Whether the cancer cells in the sample obtained from the solvated individual have one or more RET inhibitor resistance mutations; A second RET inhibitor or a second compound of formula I or a pharmaceutically acceptable salt or solvate thereof in combination with an anticancer agent is administered to an individual; or (c) if the individual has a resistance mutation that does not contain the RET inhibitor For cancer cells, other doses of the compound of formula I or a pharmaceutically acceptable salt or solvate thereof that have been previously administered to the individual are selected. In some embodiments, when selecting other doses of the compound of formula I in step (a) or a pharmaceutically acceptable salt or solvate thereof for the individual, the method may also include further selecting another anticancer agent. In some embodiments, one or more RET inhibitor resistance mutations confer increased resistance to treatment with a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, in the cancer cell or tumor. In some embodiments, the other anticancer agent is any anticancer agent known in the art. For example, the additional anticancer agent can be another RET inhibitor (eg, a second RET inhibitor). In some embodiments, the other anticancer agent may be immunotherapy. In some embodiments, the other RET inhibitor may be the compound of formula I administered in step (a), or a pharmaceutically acceptable salt or solvate thereof.

Also provided is a method for determining an individual's risk of developing a cancer having some resistance to a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, comprising: determining whether cells in a sample obtained from an individual have a or more RET inhibitor resistance mutations; and if the individual has cells containing one or more RET inhibitor resistance mutations, identifying an individual with an increased presence of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof Possibility of some resistant cancers. Also provided is a method for determining an individual's risk of developing a cancer that has some resistance to a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, comprising: identifying a patient with one or more RET inhibitor resistance mutations Individuals of the cells have an increased likelihood of developing cancers that have some resistance to the compound of formula I or a pharmaceutically acceptable salt or solvate thereof. Also provided is a method for determining the presence of a cancer having some resistance to a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, comprising: determining whether a cancer cell in a sample obtained from an individual has one or more RET Inhibitor Resistance Mutations; and Determining that Individuals Having Cancer Cells Containing One or More RET Inhibitor Resistance Mutations Have a Cancer Having Some Resistance to a Compound of Formula I or a Pharmaceutically Acceptable Salt or Solvate thereof . Also provided is a method for determining the presence in an individual of a cancer having some resistance to a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, comprising: determining the presence of cancer containing one or more RET inhibitor resistance mutations Individuals with cancer cells have a cancer that has some resistance to a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, one or more RET inhibitor resistance mutations confer increased resistance to treatment with a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, in the cancer cell or tumor.

In some embodiments of any of the methods described herein, the RET inhibitor confers increased resistance to treatment with a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, in cancer cells or tumors The resistance mutation can be any of the RET inhibitor resistance mutations listed in Table 3 or 4.

Methods of determining the level of resistance of cancer cells or tumors to a RET inhibitor, such as any of the RET inhibitors described herein or known in the art, can be determined using methods known in the art. For example, the level of resistance of cancer cells to a RET inhibitor can be measured by determining the _IC50 of a RET inhibitor, such as any of the RET inhibitors described herein or known in the art, according to the Cell viability was assessed. In other examples, the level of cancer cell resistance to a RET inhibitor can be assessed by measuring the growth rate of cancer cells in the presence of a RET inhibitor, such as any of the RET inhibitors described herein. In other examples, the level of tumor resistance to a RET inhibitor can be determined in one or more individuals over time during treatment with a RET inhibitor, such as any of the RET inhibitors described herein. To assess the mass or size of a tumor. In other examples, the level of resistance of cancer cells or tumors to RET inhibitors can be determined by assaying RET kinases comprising one or more RET inhibitor resistance mutations (i.e., the same RET expression expressed in cancer cells or tumors of an individual). Kinase) activity was assessed indirectly. Cancer cells or tumors having one or more RET inhibitor resistance mutations have a level of resistance to the RET inhibitor relative to cancer cells or tumors that do not have a RET inhibitor resistance mutation (e.g., do not have the same RET inhibitor resistance mutation cancer cells or tumors, cancer cells or tumors that do not have any RET inhibitor resistance mutations, or cancer cells or tumors expressing wild-type RET protein). For example, the measured level of resistance of cancer cells or tumors with one or more RET inhibitor resistance mutations is comparable to that of cancer cells or tumors that do not have RET inhibitor resistance mutations (e.g., do not have the same RET inhibitor resistance Mutated cancer cells or tumors, cancer cells or tumors that do not have any RET inhibitor resistance mutations, or cancer cells or tumors that express wild-type RET protein) have resistance levels that are about 1% higher, about 2% higher, about 3%, about 4% higher, about 5% higher, about 6% higher, about 7% higher, about 8% higher, about 9% higher, about 10% higher, about 11% higher, about 12% higher, about 12% higher 13% higher, about 14% higher, about 15% higher, about 20% higher, about 25% higher, about 30% higher, about 35% higher, about 40% higher, about 45% higher, about 50% higher, about 50% higher 60%, about 70% higher, about 80% higher, about 90% higher, about 100% higher, about 110% higher, about 120% higher, about 130% higher, about 140% higher, about 150% higher, about 150% higher 160%, about 170% higher, about 180% higher, about 190% higher, about 200% higher, about 210% higher, about 220% higher, about 230% higher, about 240% higher, about 250% higher, about 250% higher, about 260%, about 270% higher, about 280% higher, about 290% higher, or about 300% higher.

RET is thought to play an important role in the development and survival of afferent nociceptors in the skin and gut. RET kinase knockout mice lack enteric neurons and have other neurological abnormalities, suggesting that a functional RET kinase protein product is required during development (Taraviras, S. et al., Development , 1999, 126:2785-2797). Furthermore, in a cohort study of patients with Hirschsprung's disease characterized by colonic obstruction (due to the absence of normal colonic weakness), both familial and sporadic loss-of-function RET mutations were more prevalent (Butler Tjaden N. et al., Transl. Res. , 2013, 162: 1-15). Irritable bowel syndrome (IBS) is a common disorder affecting 10-20% of individuals in developed countries and is characterized by abnormal bowel habits, abdominal distension and visceral hypersensitivity (Camilleri, M., N. Engl. J. Med. , 2012, 367 : 1626-1635). Although the etiology of IBS is unknown, it is thought to arise from a barrier between the brain and the gastrointestinal tract, disturbance of the intestinal microflora, or increased inflammation. The resulting gastrointestinal changes interfere with normal intestinal transit, leading to diarrhea or constipation. Furthermore, in many IBS patients, sensitivity of the peripheral nervous system causes visceral hypersensitivity or pain to touch (Keszthelyi, D., Eur. J. Pain , 2012, 16: 1444-1454). See, eg, US Publication No. 2015/0099762.

Accordingly, provided herein are methods for treating those diagnosed with (or identified as having) irritable bowel syndrome (IBS) (including diarrhea-predominant, constipation-predominant or alternating bowel patterns, functional bloating, functional constipation, functional diarrhea, nonspecific Functional bowel disease, functional abdominal pain syndrome, chronic idiopathic constipation, functional esophageal disorder, functional gastric and duodenal disorder, functional anorectal pain, and inflammatory bowel disease) comprising administering to the patient A therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof.

Also provided herein are methods for use in the treatment of patients identified or diagnosed as having RET-associated irritable bowel syndrome (IBS) (e.g., using a regulatory agency-approved (e.g., FDA-approved) RET gene for identifying a patient or in a biopsy sample from a patient) , RET kinase, or a set of disorders in the expression or activity or level of any of them to identify or diagnose a patient with RET-associated irritable bowel syndrome (IBS), comprising administering to the patient a therapeutically effective amount of formula I A compound or a pharmaceutically acceptable salt or solvate thereof.

Also provided herein are methods for treating IBS-related pain comprising administering to a patient a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, is administered in combination with another therapeutic agent useful for treating one or more symptoms of IBS.

Also provided is a method for treating irritable bowel syndrome (IBS) in a patient in need thereof, the method comprising: (a) determining whether the patient's irritable bowel syndrome (IBS) is RET-related IBS (e.g., using a regulatory agency-approved (e.g., FDA) approved) for the identification of RET gene, RET kinase, or a dysregulated expression or activity or level of either in a patient or in a biopsy sample from a patient, or by performing an assay described herein without any of the limiting examples); and (b) if the IBS is determined to be RET-associated IBS, administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, the compounds of the present invention are useful for treating Irritable Bowel Syndrome (IBS) in combination with one or more other therapeutic agents or therapies that are effective in treating IBS by the same or a different mechanism of action. At least one other therapeutic agent may be part of the same or separate dosage form, together with the compound of formula I or a pharmaceutically acceptable salt or solvate thereof, via the same or different routes of administration, and based on the same or different schedules of administration, according to Standard pharmaceutical practice known to those skilled in the art is administered.

Non-limiting examples of other therapeutic agents for the treatment of irritable bowel syndrome (IBS) include probiotics, fiber supplements (e.g., psyllium, methylcellulose), antidiarrheal drugs (e.g., loperamide ( loperamide), bile acid binders (eg, cholestyramine, colestipol, colesevelam), anticholinergic and antispasmodic drugs (eg, hyoscyamine ), dicyclomine), antidepressants (e.g. tricyclic antidepressants such as imipramine or notriptyline or selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine or paroxetine), antibiotics (such as rifaximin), alosetron, and lubiprostone.

Therefore, this paper also provides a method for treating irritable bowel syndrome (IBS), which comprises administering to a patient in need a pharmaceutical combination for the treatment of IBS, the pharmaceutical combination comprising (a) a compound of formula I or a pharmaceutically acceptable compound thereof salt or solvate; (b) another therapeutic agent; and (c) optionally at least one pharmaceutically acceptable carrier for simultaneous, separate or sequential use in the treatment of IBS, wherein formula I Amounts of the compound, or a pharmaceutically acceptable salt or solvate thereof, and the other therapeutic agent are jointly effective in the treatment of IBS. In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, and the other therapeutic agent are administered simultaneously in separate dosage forms. In some embodiments, the compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, and other therapeutic agents are combined in a therapeutically effective amount, sequentially in any order in divided doses (eg, daily or intermittent doses) vote with. In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, and the other therapeutic agent are administered simultaneously in a combined dosage form.

Also provided herein is (i) a pharmaceutical combination comprising (a) a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, (b) at least one other A therapeutic agent (such as any of those described herein for the treatment of irritable bowel syndrome or exemplary other therapeutic agents known in the art) and (c) optionally at least one pharmaceutically acceptable carrier , for simultaneous, separate or sequential use in the treatment of irritable bowel disorder, wherein the compound of formula I or its pharmaceutically acceptable salt or solvate and other therapeutic agents are effective together in the treatment of irritable bowel disorder; ( ii) pharmaceutical compositions comprising such combinations; (iii) uses of such combinations for the preparation of medicaments for the treatment of irritable bowel syndrome; and (iv) commercially available packages or products comprising such combinations As a combined preparation for simultaneous, separate or sequential use; and a method of treating irritable bowel disorder in a patient in need thereof. In some embodiments, the patient is human.

As used herein, the term "pharmaceutical combination" refers to a medical therapy produced by mixing or combining more than one active ingredient and includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that the compound of formula I or a pharmaceutically acceptable salt or solvate thereof and at least one other therapeutic agent (such as an agent effective for treating irritable bowel disorder) are administered simultaneously in a single composition or dosage form with patients. The term "non-fixed combination" means that the compound of formula I or a pharmaceutically acceptable salt or solvate thereof and at least one other therapeutic agent (such as an agent effective for treating irritable bowel disorder) are formulated as a single composition or dose, This makes it possible to administer simultaneously, concurrently or sequentially to a patient in need thereof under different time constraints of intervention, wherein such administration provides effective amounts of two or more compounds in the patient. In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, and the other therapeutic agent are formulated in separate unit dosage forms, wherein the separate dosage forms are suitable for sequential or simultaneous administration. Such combinations are also suitable for combination therapy, eg administration of three or more active ingredients.

In some embodiments, the compounds provided herein are used as supportive care agents in patients undergoing cancer treatment. For example, a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, may be useful for reducing one or more symptoms associated with cancer therapy treatment, such as diarrhea or constipation complications and/or abdominal pain. See, eg, US Publication No. 2015/0099762 and Hoffman, JM et al., Gastroenterology (2012) 142:844-854. Accordingly, a compound provided herein, or a pharmaceutically acceptable salt or composition thereof, can be administered to a patient to address one or more complications associated with cancer treatment (e.g., gastrointestinal complications such as diarrhea, constipation, or abdominal pain) .

In some embodiments, a therapeutically effective amount may be administered to a patient undergoing cancer treatment (e.g., a patient experiencing adverse events associated with cancer treatment, such as immune-related adverse events or gastrointestinal complications, including diarrhea, constipation, and abdominal pain). A compound of formula I or a pharmaceutically acceptable salt or solvate thereof. For example, compounds provided herein, or pharmaceutically acceptable salts thereof, can be used to treat colitis or IBS associated with administration of checkpoint inhibitors; see, eg, Postow, MA et al., Journal of Clinical Oncology (2015) 33: 1974-1982. In some such embodiments, the compounds provided herein, or pharmaceutically acceptable salts or solvates thereof, can be formulated to exhibit low bioavailability and/or target delivery in the gastrointestinal tract. See, eg, US Patent No. 6,531,152.

Also provided is a method of inhibiting RET kinase activity in a cell comprising contacting the cell with a compound of formula I. In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is in vivo, wherein the method comprises administering to an individual having RET-containing kinase activity an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the cells are cancer cells. In some embodiments, the cancer cell is any cancer as described herein. In some embodiments, the cancer cells are RET-associated cancer cells. In some embodiments, the cells are gastrointestinal cells.

Also provided is a method of inhibiting RET kinase activity in a mammalian cell comprising contacting the cell with a compound of formula I. In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is in vivo, wherein the method comprises administering an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, to the mammal having cells comprising RET kinase activity. In some embodiments, the mammalian cells are mammalian cancer cells. In some embodiments, the mammalian cancer cell is any cancer as described herein. In some embodiments, the mammalian cancer cells are RET-associated cancer cells. In some embodiments, the mammalian cells are gastrointestinal cells.

As used herein, the term "contacting" refers to bringing together the indicated moiety in an in vitro system or in an in vivo system. For example, "contacting" a RET kinase with a compound provided herein includes administering a compound provided herein to an individual or patient having RET kinase, such as a human, and, for example, introducing a compound provided herein into a sample containing cells Or in a purified preparation containing RET kinase.

Also provided herein is a method for inhibiting cell proliferation in vitro or in vivo, the method comprising allowing cells to be treated with an effective amount of a compound of formula I as defined herein or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition thereof touch.

The phrase "effective amount" means an amount of a compound which, when administered to a patient in need of such treatment, is sufficient to: (i) treat a RET kinase-associated disease or disorder; (ii) alleviate, ameliorate, or eliminate a particular disease, condition, or one or more symptoms of a disorder; or (iii) delaying the onset of one or more symptoms of a particular disease, condition or disorder described herein. Amounts corresponding to such amounts of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof will depend on factors such as the specific compound, the disease condition and its severity, and the consistency (e.g., body weight) of the patient in need of treatment. Varies, but can usually still be determined by those skilled in the art.

When used as a medicine, the compounds of formula I (including pharmaceutically acceptable salts or solvates thereof) can be administered in the form of pharmaceutical compositions. Such compositions may be prepared in manners well known in the art of pharmacy and may be administered by a variety of routes depending upon the need for local or systemic treatment and the area to be treated. Administration can be topical (including transdermal, epidermal, ocular and mucous membranes, including intranasal, vaginal and rectal delivery), pulmonary (such as by inhalation or insufflation of powder or aerosol, including by nebulizer); intratracheal or nasal internally), orally or parenterally. Oral administration may include dosage forms formulated for once-daily or twice-daily (BID) administration. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or injection or infusion; or intracranial, eg, intrathecal or intraventricular, administration. Parenteral administration may be in the form of a bolus, or may be, for example, by means of a continuous infusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.

Also provided herein are pharmaceutical compositions comprising, as an active ingredient, a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, in combination with one or more pharmaceutically acceptable carriers (excipients). For example, a pharmaceutical composition prepared using a compound of formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compositions are suitable for topical administration. In preparing the compositions provided herein, the active ingredient is typically mixed with an excipient, diluted by the excipient or enclosed within such a carrier which takes the form of, for example, a capsule, sachet, paper or other container. When the excipient acts as a diluent, it can be a solid, semi-solid or liquid material which acts as a vehicle, carrier or medium for the active ingredient. Thus, the composition may be in the form of lozenges, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (either in solid form or in a liquid medium) medium), ointments, soft and hard gelatine capsules, sterile injectable solutions and sterile encapsulated powders containing, for example, up to 10% by weight of the active compound. In some embodiments, compositions are formulated for oral administration. In some embodiments, the composition is a solid oral formulation. In one embodiment, the composition is formulated as a tablet or capsule.

Also provided herein are pharmaceutical compositions comprising a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier. A pharmaceutical composition containing a compound of formula I or a pharmaceutically acceptable salt or solvate thereof as an active ingredient can be prepared by uniformly mixing a compound of formula I or a pharmaceutically acceptable salt thereof or Solvates are prepared with pharmaceutical carriers. The carrier can take a wide variety of forms depending on the desired route of administration (eg, oral, parenteral). In some embodiments, the composition is a solid oral composition.

Suitable pharmaceutically acceptable carriers are well known in the art. Descriptions of some of these pharmaceutically acceptable carriers can be found in The Handbook of Pharmaceutical Excipients published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain.

Methods of formulating pharmaceutical compositions have been described in numerous publications, such as Pharmaceutical Dosage Forms: Tablets , edited by Lieberman et al., Second Edition, Revised and Amplified, Volumes 1-3; Pharmaceutical Dosage Forms, edited by Avis et al. : Parenteral Medications , vol. 1-2; and Pharmaceutical Dosage Forms: Disperse Systems , ed. Lieberman et al., vol. 1-2; published by Marcel Dekker, Inc.

In preparing the compositions in oral dosage forms, any of the usual pharmaceutical media may be employed. Thus, for liquid oral preparations such as suspensions, elixirs, and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents, and the like. ; For solid oral preparations (such as powders, capsules and lozenges), suitable carriers and additives include starch, sugar, diluents, granulating agents, lubricants, binders, disintegrants and the like. Suitable binders include, but are not limited to, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium oleate, stearin Sodium Acetate, Magnesium Stearate, Sodium Benzoate, Sodium Acetate, Sodium Chloride, and Their Similarities. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, sanxian gum, and the like. Solid oral formulations may also be coated with substances such as sugars or may be provided with an enteric coating to modify the major site of absorption. For parenteral administration, the carrier usually consists of sterile water, and other ingredients may be added to enhance solubility or for preservation. Injectable suspensions or solutions may also be prepared utilizing aqueous vehicles along with suitable additives. Each dosage unit (eg, tablet, capsule, powder, injection, teaspoon, and the like) of the pharmaceutical compositions herein will contain the amount of active ingredient necessary to deliver an effective dose as described herein.

Compositions comprising a compound of formula I or a pharmaceutically acceptable salt or solvate thereof may be formulated in unit dosage forms, each dosage form containing from about 5 to about 1,000 mg (1 g), more usually from about 100 mg to about 500 mg of active Element. The term "unit dosage form" means physically discrete units suitable as unit dosages for human subjects and other patients, each unit containing a predetermined quantity of active substance calculated to produce the desired therapeutic effect in association with a suitable pharmaceutical excipient ( That is, a compound of formula I or a pharmaceutically acceptable salt or solvate thereof).

In some embodiments, the compositions provided herein contain from about 5 mg to about 50 mg of the active ingredient. Those of ordinary skill in the art will appreciate that the contemplated compounds or compositions contain about 5 mg to about 10 mg, about 10 mg to about 15 mg, about 15 mg to about 20 mg, about 20 mg to about 25 mg, about 25 mg mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg to about 45 mg, or about 45 mg to about 50 mg of active ingredient.

In some embodiments, the compositions provided herein contain from about 50 mg to about 500 mg of the active ingredient. Those of ordinary skill in the art will appreciate that the contemplated compounds or compositions contain about 50 mg to about 100 mg, about 100 mg to about 150 mg, about 150 mg to about 200 mg, about 200 mg to about 250 mg, about 250 mg mg to about 300 mg, about 350 mg to about 400 mg, or about 450 mg to about 500 mg of active ingredient. In some embodiments, the compositions provided herein contain about 10 mg, about 20 mg, about 80 mg, or about 160 mg of the active ingredient.

In some embodiments, the compositions provided herein contain from about 500 mg to about 1,000 mg of active ingredient. Those of ordinary skill in the art will appreciate that the contemplated compounds or compositions contain about 500 mg to about 550 mg, about 550 mg to about 600 mg, about 600 mg to about 650 mg, about 650 mg to about 700 mg, about 700 mg mg to about 750 mg, about 750 mg to about 800 mg, about 800 mg to about 850 mg, about 850 mg to about 900 mg, about 900 mg to about 950 mg, or about 950 mg to about 1,000 mg of active ingredient.

The daily dosage of the compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, may vary within a broad range of 1.0 to 10,000 mg or more per adult per day, or any range therein. For oral administration, the composition is preferably provided in the form of lozenges containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 160, 200 , 250 and 500 mg of active ingredient in order to adjust the dose according to the symptoms of the patient being treated. An effective amount of drug is generally supplied at a dosage level of about 0.1 mg/kg to about 1000 mg per kilogram of body weight per day, or any range therein. Preferably, the range is about 0.5 to about 500 mg/kg body weight per day, or any range therein. More preferably, about 1.0 to about 250 mg per kilogram of body weight per day, or any range therein. More preferably, about 0.1 to about 100 mg per kilogram of body weight per day, or any range therein. In one example, the range may be about 0.1 to about 50.0 mg per kilogram of body weight per day, or any amount or range therein. In another example, the range may be about 0.1 to about 15.0 mg per kilogram of body weight per day, or any range therein. In another example, the range may be from about 0.5 to about 7.5 mg per kilogram of body weight per day, or any amount to a range therein. Pharmaceutical compositions containing a compound of formula I or a pharmaceutically acceptable salt or solvate thereof may be administered on a regimen of 1 to 4 times per day or as a single daily dose.

The active compounds are effective over a wide dosage range, and are generally administered in a pharmaceutically effective amount. Optimal dosages to be administered can be readily determined by those skilled in the art. It will thus be appreciated that the actual amount of compound administered will generally be determined by the physician and will vary according to the relevant circumstances, including the mode of administration, the actual compound being administered, the strength of the formulation, the condition being treated and the progression of the disease condition. In addition, factors associated with the particular patient being treated, including patient response, age, weight, diet, time of administration, and severity of patient symptoms, will give rise to the need to adjust dosages.

In some embodiments, a compound provided herein can be administered in an amount ranging from about 1 mg/kg to about 100 mg/kg. In some embodiments, the compounds provided herein can be present at about 1 mg/kg to about 20 mg/kg, about 5 mg/kg to about 50 mg/kg, about 10 mg/kg to about 40 mg/kg, about 15 Administered in an amount of mg/kg to about 45 mg/kg, about 20 mg/kg to about 60 mg/kg, or about 40 mg/kg to about 70 mg/kg. For example, about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg kg, about 45 mg/kg, about 50 mg/kg, about 55 mg/kg, about 60 mg/kg, about 65 mg/kg, about 70 mg/kg, about 75 mg/kg, about 80 mg/kg, About 85 mg/kg, about 90 mg/kg, about 95 mg/kg, or about 100 mg/kg. In some embodiments, such administration may be once-daily or twice-daily (BID) administration.

In some embodiments, the compounds provided herein can be administered at about 10 mg twice a day (BID), 20 mg BID, about 40 mg BID, about 60 mg BID, about 80 mg BID, about 120 mg BID, about 160 mg BID And about 240 mg BID administration. In some embodiments, each dose is administered at least six hours after the previous dose. In some embodiments, each dose is administered at least twelve hours after the previous dose.

In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, exhibits pH-dependent solubility at lower pH values. Therefore, patients who are also receiving proton pump inhibitors (PPIs) and/or antacids may need to adjust the dosage form of the compound of formula I or a pharmaceutically acceptable salt or solvate thereof (such as increasing the compound of formula I or its pharmaceutically acceptable salt or solvate). above acceptable salt or solvate dosage). In some embodiments, the cytochrome P450 isoform (CUP) that metabolizes the compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, is CYP3A4. Thus, patients who are also receiving agents that inhibit or induce CYP3A4 may need to adjust the dosage form of the compound of formula I or a pharmaceutically acceptable salt or solvate thereof (e.g., in the case of a CYP3A4 inducer, increase the compound of formula I or its pharmaceutical pharmaceutically acceptable salt or solvate, or in the case of CYP3A4 inhibitors, reduce the dose of the compound of formula I or its pharmaceutically acceptable salt or solvate).

Those skilled in the art will recognize that both in vivo and in vitro assays using appropriate, known and accepted cellular and/or animal models are predictive of the ability of a test compound to treat or prevent a given condition.

Those skilled in the art will further appreciate that human clinical trials, including first-in-human dose-ranging and efficacy trials in healthy patients and/or patients with established medical conditions, can be performed according to methods well known in the clinical and medical arts .

Provided herein are pharmaceutical kits suitable for use, for example, in the treatment of RET-associated diseases or conditions, such as cancer or irritable bowel syndrome (IBS), the kits comprising one or more containers containing a pharmaceutical composition comprising A therapeutically effective amount of a compound provided herein. If desired, such kits may further comprise one or more of various conventional pharmaceutical kit components, such as containers with one or more pharmaceutically acceptable carriers, other containers, etc., as those skilled in the art This is readily apparent to those skilled in the art. Instructions, either in the form of an insert or in the form of a label, indicating the amounts of the components to be administered, directions for administration, and/or instructions for mixing the components can also be included in the kit. example

The following examples illustrate the invention.

biological example

example A

RET enzyme assay

The potency of compounds to inhibit several different RET kinase forms (wild type, V804M, M918T, G810R and G810S) was determined using CisBio's HTRF Kinease-TK assay technology. Kinase was mixed with 250 nM TK substrate biotin (CisBio _, Part Cat. No. 62TKOPEC) and test compounds were incubated under Km ATP. Compounds are typically prepared in three-fold serial dilutions in DMSO and added to the assay to give appropriate final concentrations. After incubation at 22°C for 30 minutes, the reaction was quenched by adding 8 µL of quenching solution containing 31.25 nM Sa-XL665 and 1x TK-Ab-cryptate (both from CisBio, part cat. no. 62TK0PEC ) of HTRF detection buffer. After incubation for 1 hour at 22°C, the extent of response was determined by HTRF dual-wavelength detection using a PerkinElmer EnVision multimode plate reader, and percent control (POC) was calculated using the ratiometric emission factor. 100 POC was determined using DMSO-only samples (no compound present), and 0 POC was determined using a pre-quenched control reaction. A 4 parameter logarithmic curve was fitted against the POC values as a function of compound concentration and the _IC50 value was the point where the best fitted curve intersected the 50 POC. The enzyme batches and concentrations used are shown in the table below, and the _IC50 values of the compounds tested in these assays are provided in Table 5.

example B

RET cell analysis

The cellular efficacy of compounds inhibiting RET kinase was determined in HEK-293 cells expressing the Kif5b-RET fusion protein. Briefly, HEK-293 cells expressing the Kif5b-RET fusion protein were plated at 50K cells/well in 96-well poly-D-lysine-coated dishes the day before the assay. Cells were incubated with test compounds in DMEM (Dulbecco's Modified Eagle Medium) for 1 hour at a final DMSO concentration of 0.5%. Compounds are typically prepared in three-fold serial dilutions in DMSO and added to the assay to give appropriate final concentrations. After 1 hour, the medium was removed, cells were fixed with 3.8% formaldehyde for 20 minutes, washed with PBS and permeabilized with 100% methanol for 10 minutes. Plates were then washed with PBS-0.05% Tween20 and blocked with LI-COR blocking solution (LI-COR cat# 927-40000) for 1 hour. Plates were washed with PBS-0.05% Tween20, followed by incubation with anti-phospho-RET (Tyr1062) (Santa Cruz Cat# sc-20252-R) antibody and anti-GAPDH (Millipore Cat# MAB374) antibody for 2 hours. Plates were washed with PBS-0.05% Tween20 and incubated with anti-rabbit 680 (Molecular Probes cat# A21109) and anti-mouse 800 (LI-COR cat# 926-32210) secondary antibodies for 1 hour. All antibodies were diluted in LI-COR blocking solution containing 0.05% Tween. Plates were washed with PBS-0.05% Tween20, 100 µL of PBS was added to each well, and read on a LI-COR Aerius fluorescent disc reader. Phosphorylated RET signal normalized to GAPDH signal. 100 POC (percent of control) was determined using non-test compound and 0 POC was determined using 1 µM control inhibitor. POC values were fitted to a 4 parameter logarithmic curve. The _IC50 value is the point where the curve intersects the 50 POC. The _IC50 values of the compounds tested in these assays are provided in Table 5.

example C

RET G810R and G810S mutant cell assay

The cellular potency of compounds inhibiting RET kinase was determined in HEK-293 cells expressing the G810R or G810S mutant RET Kif5b-RET fusion protein. Briefly, HEK-293 cells expressing the G810R or G810S mutant RET Kif5b-RET fusion protein were plated at 50K cells/well in 96-well poly-D-lysine-coated dishes the day before the assay . Cells were incubated with test compounds in DMEM (Dubeck's Modified Eagle's Medium) for 1 hour at a final DMSO concentration of 0.5%. Compounds are typically prepared in three-fold serial dilutions in DMSO and added to the assay to give appropriate final concentrations. After 1 hour, the medium was removed, cells were fixed with 3.8% formaldehyde for 20 minutes, washed with PBS and permeabilized with 100% methanol for 10 minutes. Plates were then washed with PBS-0.05% Tween20 and blocked with LI-COR blocking solution (LI-COR cat# 927-40000) for 1 hour. Plates were washed with PBS-0.05% Tween20 and then incubated with anti-phospho-RET (Tyr1062) (Santa Cruz cat# sc-20252-R) antibody and anti-GAPDH (Millipore cat# MAB374) antibody for 2 hours. Plates were washed with PBS-0.05% Tween20 and incubated with anti-rabbit 680 (Molecular Probes cat# A21109) and anti-mouse 800 (LI-COR cat# 926-32210) secondary antibodies for 1 hour. All antibodies were diluted in LI-COR blocking solution containing 0.05% Tween. Plates were washed with PBS-0.05% Tween20, 100 µL of PBS was added to each well, and read on a LI-COR Aerius fluorescent disc reader. Phosphorylated RET signal normalized to GAPDH signal. 100 POC (percent of control) was determined using non-test compound and 0 POC was determined using 1 µM control inhibitor. POC values were fitted to a 4 parameter logarithmic curve. The _IC50 value is the point where the curve intersects the 50 POC. The _IC50 values of the compounds tested in these assays are provided in Table 5. Table 5. _IC50 of the compounds tested in the assays of Examples AC. ND = not determined.

synthetic example

Preparation of synthetic intermediates

intermediate P1

3-(4- chlorine -7-( Phenylsulfonyl )-7H- pyrrolo [2,3-d] pyrimidine -5- base )-5- Cyclopropylisoxazole

Step 1: Preparation of 4- chloro -7H- pyrrolo [2,3-d] pyrimidine -5- carbaldehyde . To 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (2.32 g, 9.98 mmol) in THF (50 mL) cooled to -78 °C under _{N2 ( g )} atmosphere To the suspension of n-BuLi (2.5 M, hexane) (9.2 mL, 23.0 mmol) was added dropwise. The reaction was stirred for 1 h, then DMF (1.00 mL, 13.0 mmol) was introduced dropwise. After stirring for an additional 30 min at -78 °C, the reaction was allowed to warm slowly to room temperature, then quenched with sat _{. NH4Cl ( aq )} and water. The biphasic mixture was concentrated in vacuo to remove organic solvent, and the resulting suspension was filtered. The solid was collected and rinsed with water and hexanes, and then dried in vacuo to give the title compound (1.52 g, 84% yield).

Step 2: Preparation of 4- chloro -7-( phenylsulfonyl )-7H- pyrrolo [2,3-d] pyrimidine -5- carbaldehyde . A solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde (400 mg, 2.2 mmol) in DMF (11 mL) was treated with 60 wt% NaH (110 mg, 2.75 mmol) and Stir at room temperature for 15 minutes. The resulting yellow solution was treated dropwise with benzenesulfonyl chloride (340 µL, 2.6 mmol). After stirring at room temperature for 20 minutes, the reaction mixture was quenched with ice (2 g) and water (20 mL). The quenched mixture was stirred at room temperature for 3 minutes and the resulting suspension was filtered. The collected solids were rinsed with water (10 mL) and hexanes (10 mL) and air dried to give the title compound (650 mg, 92% yield).

Step 3: Preparation of 4- chloro -7-( phenylsulfonyl )-7H- pyrrolo [2,3-d] pyrimidine -5- carbaldehyde oxime . Stir 4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde (650 mg, 2.0 mmol), NH ₂ OH ∙ HCl (170 mg, 2.4 mmol) and a mixture of NaOAc (200 mg, 2.4 mmol) in EtOH (20 mL) for 20 hours. The resulting mixture was diluted with DCM (20 mL), and the resulting suspension was filtered through a pad of Celite®. The filtrate was concentrated in vacuo to afford the title compound (680 mg, quantitative yield).

Step 4: Preparation of 3-(4- chloro -7-( phenylsulfonyl )-7H- pyrrolo [2,3-d] pyrimidin -5- yl )-5- cyclopropylisoxazole . 4-Chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde oxime (170 mg, 0.505 mmol), NCS (80.9 mg, 0.606 mmol), KHCO _{3 ( solid )} (92 mg, 1.52 mmol) and cyclopropylacetylene (128 μL, 1.51 mmol) in DMF (5.048 mL) for 45 minutes. After cooling to room temperature, the reaction mixture was diluted with EtOAc and then quenched with water. The resulting suspension was filtered and the solid was washed with EtOAc and water. The biphasic filtrate was separated and the organic extract was concentrated in vacuo. The crude residue was purified by silica chromatography (0-30% EtOAc/hexanes) to afford the title compound (101 mg, 50% yield). MS (apci) m/z = 401.0 (M+H).

intermediate P2

7-( tertiary butyl )-4- chlorine -7H- pyrrolo [2,3-d] pyrimidine

A solution of 2-(4,6-dichloropyrimidin-5-yl)acetaldehyde (5.00 g, 25.4 mmol) in 2-methoxyethan-1-ol (25.4 mL) was successively washed with 2-methylpropan- 2-Amine hydrochloride (4.80 mL, 30.5 mmol) and DIEA (13.3 mL, 76.2 mmol). The resulting mixture was stirred overnight at 70 °C. After cooling to room temperature, the reaction mixture was partially concentrated in vacuo. The residual mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were filtered through PS paper and concentrated in vacuo. The crude residue was purified by silica chromatography (0-50% EtOAc/hexanes) to afford the title compound (4.20 g, 79% yield). MS (apci) m/z = 210.1 (M+H).

intermediate P3

7-( tertiary butyl )-5- iodine -7H- pyrrolo [2,3-d] pyrimidine -4- amine

Step 1: Preparation of 7-( tert-butyl )-4- chloro -5- iodo -7H- pyrrolo [2,3-d] pyrimidine . Cold (0°C) 7-(tert-butyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidine ( intermediate P2 ; 2.68 g, 12.8 mmol) in DMF (25 mL). The reaction was covered with aluminum foil, stirred at room temperature overnight and then quenched with sat. NaHCO _{3 ( aq )} and EtOAc. After phase separation, the organic extracts were washed with water and brine, then concentrated and purified by silica chromatography (0-30% EtOAc/hexanes) to afford the title compound (3.62 g, 79% yield). MS (apci) m/z = 336.0 (M+H).

Step 2: Preparation of 7-( tert-butyl )-5- iodo -7H- pyrrolo [2,3-d] pyrimidin -4- amine . In a Parr pressure vessel, mix 7-(tert-butyl)-4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (3.62 g, 10.8 g) in THF (12.4 mL) and _NH4OH (12.4 mL, 10.8 mmol), sealed and stirred first at 120 °C for 16 hours, and then at room temperature for 48 hours. The reaction mixture was diluted with water and filtered to afford the title compound (3.53 g, quantitative yield). MS (apci) m/z = 317.0 (M+H).

intermediate P4

7-(2- Cyclopropylpropane -2- base )-5- Ethynyl -7H- pyrrolo [2,3-d] pyrimidine -4- amine

Step 1: Preparation of 4- chloro -7-(2- cyclopropylpropan- 2- yl )-7H- pyrrolo [2,3-d] pyrimidine . A solution of 2-(4,6-dichloropyrimidin-5-yl)acetaldehyde (1.38 g, 7.00 mmol) in EtOH (10 mL) was treated with DIEA (4.88 mL, 28.0 mmol) and stirred at room temperature for 10 minutes, followed by the introduction of 2-cyclopropylpropan-2-amine hydrochloride (1.0 g, 7.00 mmol). The resulting mixture was stirred overnight at 90 °C. After cooling to room temperature, the reaction mixture was concentrated, diluted with water and extracted with EtOAc. The organic extracts were concentrated and purified by silica chromatography (5-30% EtOAc/hexanes) to afford the title compound (1.49 g, 90% yield). MS (apci) m/z = 236.1 (M+H).

Step 2: Preparation of 4- chloro -7-(2- cyclopropylpropan- 2- yl )-5- iodo -7H- pyrrolo [2,3-d] pyrimidine . In a container covered with aluminum foil, 4-chloro-7-(2-cyclopropylprop-2-yl)-7H-pyrrolo[2,3-d]pyrimidine (1.49 g, 6.32 mmol) in DMF (13.1 mL ) was treated with NIS (2.19 g, 9.76 mmol) and stirred overnight at room temperature. The reaction mixture was concentrated in vacuo. The resulting residue was diluted with saturated NaHCO _{3 ( aq )} and 10% Na ₂ S ₂ O _{3 ( aq )} and extracted with DCM. The organic extracts were dried over anhydrous Na ₂ SO _{4 ( solid )} , filtered and concentrated. The crude residue was purified by silica chromatography (0-30% EtOAc/hexanes) to afford the title compound (2.19 g, 96% yield). MS (apci) m/z = 362.0 (M+H).

Step 3: Preparation of 7-(2- cyclopropylpropan- 2- yl )-5- iodo - 7H- pyrrolo [2,3-d] pyrimidin -4- amine . In a pressure vessel, treat 4-chloro-7-(2-cyclopropylpropan-2-yl)-5-iodo-7H-pyrrolo[2,3-d with _NH4OH (7.6 mL, 6.06 mmol) ] A solution of pyrimidine (2.19 g, 6.06 mmol) in THF (7.6 mL). The reaction vessel was sealed and the reaction mixture was stirred overnight at 120 °C. After cooling to room temperature, the reaction mixture was diluted with water and then extracted with EtOAc. The organic extract was dried over anhydrous Na ₂ SO _{4 ( solid )} , filtered and concentrated in vacuo to give the title compound which was used directly in the next step without further purification (1.5 g, 72% yield). MS (apci) m/z = 343.0 (M+H).

Step 4: Preparation of 7-(2- cyclopropylpropan- 2- yl )-5-(( trimethylsilyl ) ethynyl )-7H- pyrrolo [2,3-d] pyrimidin -4- amine . In a pressure vessel, 7-(2-cyclopropylpropan-2-yl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (1.4 g, 4.09 mmol), CuI ( A mixture of 195 mg, 1.02 mmol) and PdCl ₂ ( PPh ₃ ) ₂ (287 mg, 0.409 mmol) in DMF (4 mL) and TEA (1 mL) was purged with Ar _{( g )} , followed by ethynyltrimethyl base silane (850 µL, 6.14 mmol). After sealing and stirring at room temperature for 18 hours, the reaction mixture was diluted with DCM and washed with water and brine. The organic layer was dried over anhydrous Na ₂ SO _{4 ( solid )} , filtered and concentrated in vacuo. The crude residue was purified by silica chromatography (0-10% MeOH/DCM) to afford the title compound (300 mg, 24% yield). MS (apci) m/z = 313.2 (M+H).

Step 5: Preparation of 7-(2- cyclopropylprop- 2- yl )-5- ethynyl - 7H- pyrrolo [2,3-d] pyrimidin -4- amine . At 0°C, to 7-(2-cyclopropylprop-2-yl)-5-((trimethylsilyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidine-4- To a solution of the amine (300 mg, 0.960 mmol) in THF (6.4 mL) was added TBAF (2.88 mL, 2.88 mmol). After stirring at the same temperature for 2 hours, the reaction mixture was quenched with water and extracted with EtOAc. The organic extracts were dried over anhydrous Na ₂ SO _{4 ( solid )} , filtered and concentrated in vacuo to afford the title compound (200 mg, 94% yield). MS (apci) m/z = 241.2 (M+H).

intermediate P7

3-(4- chlorine -7- Isopropyl -7H- pyrrolo [2,3-d] pyrimidine -5- base )-5- Cyclopropylisoxazole -4- ethyl formate

Step 1: Preparation of 4- chloro -7- isopropyl -7H- pyrrolo [2,3-d] pyrimidine -5- carbaldehyde . ₄ -Chloro- _7H -pyrrolo[ _{2,3 - d} ]pyrimidine-5-carbaldehyde (3.6 g, 19.8 mmol) in DMF (40 mL). Next, the reaction mixture was stirred overnight at 50 °C. After cooling to room temperature, the reaction was diluted with water (100 mL) and filtered. The filter cake was rinsed with water (30 mL) and then air dried to give the title compound (3.1 g, 70% yield) as an off-white solid. MS (apci) m/z = 224.1 (M+H).

Step 2: Preparation of 4- chloro -7- isopropyl -7H- pyrrolo [2,3-d] pyrimidine -5- carbaldehyde oxime . 4-Chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde (1.15 g, 5.14 mmol), NH ₂ OH-HCl (0.39 g, 5.66 mmol) were stirred at 50 °C ) and NaOAc (0.46 g, 5.66 mmol) in EtOH (26 mL) for 30 min. After cooling to room temperature, the reaction was diluted with DCM (50 mL) and filtered through a pad of celite. The filtrate was concentrated in vacuo to afford the title compound (1.25 g, quantitative yield) as a pale yellow solid. MS (apci) m/z = 239.1 (M+H).

Step 3: Preparation of ethyl 3-(4- chloro -7- isopropyl -7H- pyrrolo [2,3-d] pyrimidin -5- yl )-5- cyclopropylisoxazole -4- carboxylate . In a pressure vessel, 4-chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde oxime (96.6 mg, 0.40 mmol) was treated with NCS (59.4 mg, 0.44 mmol) in Solution in 1,2-dimethoxyethane (8.1 mL). The vessel was then sealed and the reaction was stirred overnight at room temperature. Ethyl 3-cyclopropylpropanoate ( Intermediate R1 ) (559 μL, 4.05 mmol) and KHCO ₃ (122 mg, 1.21 mmol) were then introduced, and the reaction was resealed and heated at 65° C. for 2 hours. Next, the reaction mixture was filtered. The filtrate was concentrated and purified by silica chromatography (0-70% EtOAc/hexanes as gradient eluent) to afford the title compound (82.4 mg, 54% yield). MS (apci) m/z = 375.1 (M+H).

intermediate P11

(4- chlorine -7- Isopropyl -7H- pyrrolo [2,3-d] pyrimidine -6- base ) Methanol

Step 1: Preparation of ethyl 4- chloro -7- isopropyl -7H- pyrrolo [2,3-d] pyrimidine - 6-carboxylate . A solution of ethyl 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate (1.56 g, 6.91 mmol) in THF (70 mL) was treated with iPrOH (794 µL, 10.4 mmol) and PPh ₃ (2.72 g, 10.4 mmol) was treated, and the resulting mixture was then cooled to 0 °C. The cold (0 °C) mixture was treated dropwise with DIAD (2.04 mL, 10.4 mmol) and stirred at room temperature for 16 hours. The resulting mixture was concentrated in vacuo. The crude residue was purified by silica chromatography (5-60% hexane-EtOAc as gradient eluent) to afford the title compound (1.76 g, 95% yield). MS (apci) m/z = 268.1 (M+H).

Step 2: Preparation of (4- chloro -7- isopropyl -7H- pyrrolo [2,3-d] pyrimidin -6- yl ) methanol . Cold (-78 °C) ethyl 4-chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate (1.76 g, 6.57 mmol) in DCM (66 mL) The solution was treated with DIBAL-H (25 wt% in toluene; 13.3 mL, 19.7 mmol) and stirred at -78 °C for 30 min. The cold (-78 °C) reaction mixture was quenched by the addition of aqueous potassium sodium tartrate (1.0 M, approximately 50 mL). The quenched mixture was then stirred at room temperature for 60 hours, then diluted with additional water. The biphasic mixture was extracted with DCM (2x). The organic extracts were combined, dried over anhydrous Na ₂ SO _{4 ( solid )} , filtered and concentrated in vacuo. The crude residue was purified by silica chromatography (5-60% hexane-acetone as gradient eluent) to afford the title product (1.43 g, 96% yield). MS (apci) m/z = 226.1 (M+H).

intermediate P13

6-((( tert- butyldimethylsilyl ) oxy ) methyl )-4- chloro -5- iodo -7- isopropyl -7H- pyrrolo [2,3-d] pyrimidine

Step 1: Preparation of (4- chloro -5- iodo -7- isopropyl -7H- pyrrolo [2,3-d] pyrimidin -6- yl ) methanol . (4-Chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)methanol ( intermediate P11 ) (1.43 g, 6.34 mmol) was treated with NIS (1.57 g, 6.97 mmol) ) in DMF (25 mL), and then the mixture was stirred at room temperature for 16 hours. The resulting mixture was diluted with water and extracted with EtOAc (2x). The combined organic extracts were washed with water (3×) and brine (1×) and then dried over anhydrous Na ₂ SO _{4 ( solid )} , filtered and concentrated in vacuo to afford the title compound (2.12 g, 95% yield). MS (apci) m/z = 352.0 (M+H).

Step 2: Preparation of 6-((( tert-butyldimethylsilyl ) oxy ) methyl )-4- chloro -5- iodo -7- isopropyl -7H- pyrrolo [2,3-d ] pyrimidine . (4-Chloro-5-iodo-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl was treated with TBDMSCl (1.36 g, 9.05 mmol) and imidazole (821 mg, 12.1 mmol) ) a solution of methanol (2.12 g, 6.03 mmol) in DMF (30 mL), and then stirred at room temperature for 1 hour. The resulting mixture was quenched with water and extracted with EtOAc (2x). The combined organic extracts were washed with water (3×) and brine (1×), then dried over anhydrous Na ₂ SO _{4 ( solid )} , filtered and concentrated in vacuo. The crude residue was purified by silica chromatography (5-50% hexane-EtOAc as gradient eluent) to afford the title compound (2.58 g, 92% yield). MS (apci) m/z = 466 (M+H).

intermediate P14

6-((( tert-butyldimethylsilyl ) oxy ) methyl )-N-(2,4- dimethoxybenzyl )-5- iodo -7- isopropyl -7H- Pyrrolo [2,3-d] pyrimidin -4- amine

Treatment of 6-(((tert-butyldimethylsilyl)oxy)methyl)-4-chloro-5-iodo with 2,4-dimethoxybenzylamine (1.201 mL, 7.996 mmol) - A solution of 7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine ( intermediate P13 ; 1.49 g, 3.20 mmol) in DMSO (13 mL), and then the resulting mixture was stirred at 60 °C 16 Hour. After cooling to room temperature, the reaction mixture was diluted with water and extracted with EtOAc (2x). The combined organic extracts were washed with water (3×) and brine (1×), then dried over anhydrous Na ₂ SO _{4 ( solid )} , filtered and concentrated in vacuo. The crude residue was purified by silica chromatography (5-75% MTBE/hexanes) to afford the title compound (1.88 g, 99% yield). MS (apci) m/z = 597.1 (M+H).

intermediate P18

3-(4- chlorine -7H- pyrrolo [2,3-d] pyrimidine -5- base )-5- Cyclopropylisoxazole

To a solution of tetrabutylammonium fluoride (TBAF) in THF (1 M) (14.6 mL, 14.6 mmol) was added 3-(4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[ 2,3-d]pyrimidin-5-yl)-5-cyclopropylisoxazole ( intermediate P1 ) (2.93 g, 7.31 mmol). The mixture was heated at 60 °C for 1 h, then cooled to room temperature, diluted with EtOAc (50 mL) and washed with water (2 x 30 mL). After phase separation, the organic layer was dried ( _Na2SO4 ), filtered and concentrated to give the title product as a beige solid, assuming quantitative _yield . MS (apci neg) m/z = 259.1 (MH).

Intermediate P19

(3-(4- chlorine -7- Isopropyl -7H- pyrrolo [2,3-d] pyrimidine -5- base )-5- Cyclopropylisoxazole -4- base ) Methanol

Cold (-78°C) 3-(4-chloro-7-isopropyl-7H-pyrrolo[2,3- d] Ethyl pyrimidin-5-yl)-5-cyclopropylisoxazole-4-carboxylate ( intermediate P7 ; 128 mg, 0.342 mmol) in DCM (1.366 µL). After stirring the resulting mixture at -78°C for 30 minutes, additional DIBAL-H (230 µL, 0.34 mmol) was introduced. The mixture was stirred for an additional 30 minutes at -78°C, then quenched with water. The aqueous phase of the quench was solidified at -78°C, and the organic phase was separated by decantation. The organic extract was washed sequentially with water and brine, then passed through a phase separator column and concentrated in vacuo to afford the title compound (100.6 mg, 89% yield). MS (apci) m/z = 333.1 (M+H).

intermediate P20

5-(5- Cyclopropylisoxazole -3- base )-7H- pyrrolo [2,3-d] pyrimidine -4- amine

In a sealed pressure vessel, heat 3-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-5-cyclopropylisoxazole ( intermediate P18 ) at 100 °C (1.04 g, 3.99 mmol) and a mixture of concentrated _NH4OH (5 mL) in 1,4-dioxane (10 mL) for 2 hours. After cooling to room temperature, the mixture was concentrated to dryness, then triturated with water (10 mL) and filtered to afford the title product ( 0.82 g, 85 %) as a beige solid after drying. MS (apci) m/z = 242.2 (M+H).

intermediate P21

6-( Aminomethyl )-N-(2,4- Dimethoxybenzyl )-7- Isopropyl -5-(3- methyl -1H- pyrazole -5- base )-7H- pyrrolo [2,3-d] pyrimidine -4- amine

Step 1: Preparation of 6-((( tert-butyldimethylsilyl ) oxy ) methyl )-N-(2,4 -dimethoxybenzyl )-7- isopropyl -5- (3- Methyl -1H- pyrazol -5- yl )-7H- pyrrolo [2,3-d] pyrimidin -4- amine . In a sealed pressure vessel, heat 6-(((tert-butyldimethylsilyl)oxy)methyl)-N-(2,4-dimethoxybenzyl)- 5-iodo-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine ( intermediate P14 ) (0.60 g, 1.0 mmol), 3-methyl-5-(4,4 ,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)-1H-pyrazole (0.27 g, 1.3 mmol), (PPh ₃ ) ₂ Pd(II)Cl ₂ (0.14 g, 0.20 mmol) and _{Na2CO3 ( aq )} (2 M) (1.5 mL, _3.0 mmol) in 1,4-dioxane (10 mL) for 15 hours. The mixture was cooled to room temperature, then concentrated and purified by silica chromatography (0-80% EtOAc/Hexanes) to afford the title compound (0.33 g, 60%) as a light brown oil. MS (apci) m/z = 551.3 (M+H).

Step 2: Preparation of (4-((2,4- dimethoxybenzyl ) amino )-7- isopropyl -5-(3- methyl -1H- pyrazol -5- yl )-7H -pyrrolo [2,3-d] pyrimidin - 6 - yl ) methanol . At room temperature, to 6-(((tert-butyldimethylsilyl)oxy)methyl)-N-(2,4-dimethoxybenzyl)-7-isopropyl- Solution of 5-(3-methyl-1H-pyrazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.33 g, 0.60 mmol) in THF (3.0 mL) Added TBAF (1 M, THF) (0.72 mL, 0.72 mmol) and stirred for 15 minutes. Another portion of TBAF (0.18 mL, 0.18 mmol) was added. The reaction was stirred for an additional 15 minutes, then diluted with EtOAc (10 mL). It was then washed with water (2 x 10 mL) and brine, dried ( _Na2SO4 ) _, filtered and concentrated to a solid residue which was triturated with hexanes to give the title compound (0.15 g, 57%) as a white solid. MS (apci) m/z = 437.2 (M+H).

Step 3: Preparation of 6-( azidomethyl )-N-(2,4 -dimethoxybenzyl )-7- isopropyl -5-(3- methyl -1H- pyrazole -5 -yl ) -7H- pyrrolo [2,3-d] pyrimidin -4- amine . To (4-((2,4-dimethoxybenzyl)amino)-7-isopropyl-5-(3-methyl-1H-pyrazol-5-yl)-7H-pyrrolo To a suspension of [2,3-d]pyrimidin-6-yl)methanol (131 mg, 0.30 mmol) in toluene (3.0 mL), diphenylphosphoryl azide (97 µL, 0.45 mmol) and 2, 3,4,6,7,8,9,10-Octahydropyrimido[1,2-a]azepine (67 µL, 0.45 mmol). After stirring at room temperature for 15 hours, the reaction mixture was concentrated and purified by silica chromatography (0-100% EtOAc/hexanes) to afford the title compound (80 mg, 58%) as a white solid. MS (apci) m/z = 462.2 (M+H).

Step 4: Preparation of 6-( aminomethyl )-N-(2,4- dimethoxybenzyl )-7- isopropyl -5-(3- methyl- 1H- pyrazole -5- base )-7H- pyrrolo [2,3-d] pyrimidin -4- amine . 6-(Azidomethyl)-N-(2,4-dimethoxybenzyl)-7-isopropyl-5-(3-methanol) was stirred under a hydrogen-filled balloon at room temperature Base-1H-pyrazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (75 mg, 0.16 mmol) and Pd/C (10% by weight) (17 mg, 0.016 mmol ) in MeOH (3.2 mL) for 15 hours. The mixture was filtered through a short pad of celite and the filtrate was concentrated to give the title compound (70 mg, 99%) as a white solid. MS (apci) m/z = 436.3 (M+H).

intermediate R1

3- Ethyl cyclopropylpropionate

A solution of ethynylcyclopropane (0.78 g, 11.8 mmol) in THF (8 mL) was bubbled with Ar _{( g )} and cooled to -78 °C, followed by the dropwise addition of n-BuLi (2.5 M in THF; 5.2 mL , 13.0 mmol). The mixture was stirred at -78°C for 30 minutes and at -10°C for 45 minutes. Then, the reaction mixture was recooled to -78 °C, followed by the dropwise addition of ethyl chloroformate (1.24 mL, 13.0 mmol). The resulting mixture was allowed to warm to room temperature, then stirred overnight, then partitioned between EtOAc and sat. _{NH4Cl ( aq )} . After phase separation, the organic layer was washed with water, then dried over anhydrous Na ₂ SO _{4 ( solid )} , filtered and concentrated in vacuo to afford the title compound (1.6 g, 98% yield). MS (apci) m/z = 139.1 (M+H).

Preparation of synthetic examples

example 1

5-(5- Cyclopropyl -4- Iodoisoxazole -3- base )-7- Isopropyl -7H- pyrrolo [2,3-d] pyrimidine -4- amine

Step 1: Preparation of 3-(4- chloro -7-( phenylsulfonyl )-7H- pyrrolo [2,3-d] pyrimidin -5- yl )-5- cyclopropyl -4- iodoisoxa azole . 3-(4-Chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-5-cyclopropylisoxazole ( middle P1 ; 90 mg, 0.22 mmol) and NIS (61 mg, 0.27 mmol) in TFA (1 mL) for 1 hour, then concentrated, washed with saturated NaHCO _{3 ( aq )} and 10% Na ₂ S ₂ O _{3 ( aqueous solution )} and extracted with DCM. The organic extracts were dried over anhydrous Na ₂ SO _{4 ( solid )} , filtered and concentrated in vacuo to afford the title compound (116 mg, 98% yield).

Step 2: Preparation of 5-(5- cyclopropyl -4- iodoisoxazol - 3- yl )-7H- pyrrolo [2,3-d] pyrimidin -4- amine . 3-(4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-5-cyclopropyl-4-iodoisoxazole (116 mg, 0.220 mmol) and _NH3 (2 M, iPrOH) (2.20 mL, 4.4 mmol) was sealed in a pressure vessel and stirred at 90 °C for 16 h. After cooling to room temperature, the reaction mixture was treated with 2 M NaOH _{( aq )} (550 µL, 1.10 mmol) and MeOH (2.20 mL). The resulting mixture was stirred at 60 °C for 30 min, then cooled to room temperature and concentrated in vacuo. The crude material was triturated with water (10 mL), filtered and air dried to afford the title compound (63 mg, 78% yield).

Step 3: Preparation of 5-(5- cyclopropyl -4- iodoisoxazol -3- yl )-7- isopropyl- 7H- pyrrolo [2,3-d] pyrimidin -4- amine . Treatment of 5-(5-cyclopropyl-4-iodoisoxazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine with 60 wt% NaH (10 mg, 0.25 mmol) (63 mg, 0.17 mmol) in DMF (1.01 mL). After stirring at room temperature for 15 minutes, the resulting solution was treated with 2-iodopropane (51 µL, 0.51 mmol) and stirred at room temperature for an additional 4 hours. The reaction mixture was quenched with water and extracted with EtOAc. The organic extracts were dried over anhydrous Na ₂ SO _{4 ( solid )} , filtered and concentrated in vacuo. The crude residue was purified by silica chromatography (0-75% EtOAc/hexanes) to afford the title compound (27 mg, 38% yield). MS (apci) m/z = 410.0 (M+H).

example 2

5-(5- Cyclopropyl -4-( pyridine -2- base ) Isoxazole -3- base )-7- Isopropyl -7H- pyrrolo [2,3-d] pyrimidine -4- amine

In a pressure vessel, 5-(5-cyclopropyl-4-iodoisoxazol-3-yl)-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine ( Example 1 ; 25 mg, 0.061 mmol), 2-(tributylstannyl)pyridine (34 mg, 0.092 mmol), PdCl ₂ [ P ( cy ) ₃ ] ₂ (6.8 mg, 0.0092 mmol) and CsF (19 mg, 0.12 mmol) in toluene (611 µL) was bubbled with Ar _{( g )} , sealed and stirred at 100°C for 15 hours, then at 110°C for 6 hours. After cooling to room temperature, the reaction mixture was concentrated and purified by reverse phase chromatography (0-95% ACN/water with 0.1% TFA). The desired fractions were combined and concentrated in vacuo to remove most of the ACN. The resulting aqueous solution was treated with saturated NaHCO _{3 ( aq )} and extracted with DCM. The organic extracts were dried over anhydrous Na ₂ SO _{4 ( solid )} , filtered and concentrated in vacuo. The free base residue required repurification by silica chromatography (0-8% MeOH/DCM) to afford the title compound (3.5 mg, 16% yield). MS (apci) m/z = 361.2 (M+H).

example 3

5-(5- Cyclopropylisoxazol -3- yl ) -7- isopropyl -7H- pyrrolo [2,3-d] pyrimidin -4- amine

Step 1: Preparation of 5-(5- cyclopropylisoxazol -3- yl )-7-( phenylsulfonyl )-7H- pyrrolo [2,3-d] pyrimidin -4- amine . In a sealed tube, stir 3-(4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-5-cyclopropyl A mixture of isoxazole ( Intermediate P1 ; 55 mg, 0.14 mmol) and _NH3 (2 M, iPrOH) (1.4 mL, 2.7 mmol) for 1 h. The reaction mixture was cooled to room temperature and then concentrated in vacuo to afford the title compound (50 mg, 96% yield). MS (apci) m/z = 382.0 (M+H).

Step 2: Preparation of 2,2,2- trifluoroacetic acid 5-(5- cyclopropylisoxazol- 3- yl )-7H- pyrrolo [2,3-d] pyrimidin -4- amine . In a sealed tube, stir 5-(5-cyclopropylisoxazol-3-yl)-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine- _A mixture of 4-amine (50 mg, 0.13 mmol) and _{K2CO3 ( aq )} (54 mg, 0.39 mmol) in MeOH (2.60 mL) for 30 min. After cooling to room temperature, the reaction mixture was concentrated in vacuo. The resulting residue was purified by reverse phase chromatography (0-95% ACN/water with 0.1% TFA) to afford the title compound (27 mg, 86% yield).

Step 3: Preparation of 5-(5- cyclopropylisoxazol- 3- yl )-7- isopropyl -7H- pyrrolo [2,3-d] pyrimidin -4- amine . 2,2,2-Trifluoroacetic acid 5-(5-cyclopropylisoxazol-3-yl)-7H-pyrrolo[2,3-d] was treated with 60 wt% NaH (4.8 mg, 0.12 mmol) Suspension of pyrimidin-4-amine (24 mg, 0.099 mmol) in DMF (995 µL). After stirring at room temperature for 15 minutes, the resulting solution was treated with 2-iodopropane (30 µL, 0.30 mmol) and stirred at room temperature for an additional 22 hours. The reaction mixture was then treated with another 60 wt% NaH (4 mg, 0.10 mmol) and stirred at room temperature for 30 minutes. The mixture was quenched with water and extracted with EtOAc. The organic extracts were concentrated and purified by silica chromatography (0-100% EtOAc/hexanes) to afford the title compound (9 mg, 32% yield). MS (apci) m/z = 284.1 (M+H).

example 4

7-( tertiary butyl )-5-(5- Cyclopropylisoxazole -3- base )-7H- pyrrolo [2,3-d] pyrimidine -4- amine

Step 1: Preparation of 7-( tert-butyl )-4- chloro -7H- pyrrolo [2,3-d] pyrimidine -5- carbaldehyde . 7-(tert-butyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidine ( intermediate P2 ; 1.2 g, 5.72 mmol) was treated dropwise with POCl ₃ (786 µL, 8.58 mmol) ) in DMF (11.4 mL). The reaction mixture was stirred overnight at room temperature and then at 50 °C for 2 hours. The mixture was cooled to 0 °C and 14.5 M _NH4OH (1.58 mL, 22.9 mmol) was added dropwise. The resulting mixture was stirred at room temperature for 2 days, then quenched with water (50 mL). Then, the quenched mixture was extracted with EtOAc (2 x 100 mL). The combined organic extracts were filtered through PS paper and concentrated in vacuo. The residue was purified by silica chromatography (0-10% EtOAc/hexanes) to afford the title compound (450 mg, 33% yield).

Step 2: Preparation of 4- amino -7-( tert-butyl )-7H- pyrrolo [2,3-d] pyrimidine -5- carbaldehyde . In a pressure vessel, NH ₄ OH (14.5 M, 986.5 µL, 14.30 mmol), 7-(tert-butyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde (340 mg, 1.43 mmol) and NaOAc (235 mg, 2.86 mmol) in 2-methoxyethan-1-ol (2.86 mL) was stirred at 60°C for 8 hours, then at 120°C for 2 hours. The reaction mixture was treated with DIEA (748 µL, 4.29 mmol) and stirred at 120 °C overnight. After cooling to room temperature, the reaction mixture was treated with 1 M HCl _{( aq )} (22 mL, 22 mmol). Next, the aqueous mixture was extracted with DCM (3 x 20 mL) in PS Frit. The combined organic extracts were concentrated in vacuo to afford the title compound (300 mg, 96% yield). MS (apci) m/z = 219.2 (M+H).

Step 3: Preparation of (E)-4- amino -7-( tert-butyl )-7H- pyrrolo [2,3-d] pyrimidine -5- carbaldehyde oxime . 4-Amino-7-(tert-butyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde (200 mg, 0.916 mmol), NH ₂ OH (151 mg, 4.58 mmol) and NaOAc (150 mg, 1.83 mmol) in 2-methoxyethan-1-ol (1.83 mL) overnight. After cooling to room temperature, the reaction mixture was partially concentrated in vacuo and then treated with ice water (5 mL). The resulting aqueous mixture was extracted in PS Frit with DCM (3 x 20 mL) and the organic extracts were concentrated in vacuo to afford the title compound (101 mg, 47% yield). MS (apci) m/z = 234.1 (M+H).

Step 4: Preparation of 7-( tert-butyl )-5-(5- cyclopropylisoxazol -3- yl )-7H- pyrrolo [2,3-d] pyrimidin -4- amine . Stir (E)-4-amino-7-(tert-butyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde oxime (20 mg, 0.086 mmol) and NaOCl ( 6.4 mg, 0.086 mmol) in ACN (1.0 mL) for 3 days, followed by stirring at 60°C for 8 hours. After cooling to room temperature, the reaction mixture was treated with additional NaOCl (6.4 mg, 0.086 mmol) and cyclopropylacetylene (14.1 μL, 0.17 mmol). The resulting mixture was stirred at room temperature for 6 days. Then, the reaction mixture was diluted with water (1 mL) in PS Frit and extracted with DCM (3×). The combined organic extracts were concentrated in vacuo and the crude residue was purified by reverse phase chromatography (0-50% ACN/water) to afford the title compound (2.2 mg, 9% yield). MS (apci) m/z = 298.1 (M+H).

example 5

7-( tert-butyl )-5-(1- cyclopropyl -1H- pyrazol- 4- yl )-7H- pyrrolo [2,3-d] pyrimidin -4- amine

In a pressure vessel, 7-(tert-butyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine ( Intermediate P3 ; 30 mg, 0.0949 mmol), Pd(PPh ₃ ) ₄ (11.0 mg, 0.00949 mmol), 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1H-pyridine A mixture of azole (28.9 mg, 0.123 mmol) and 2 M Na ₂ CO _{3 ( aq )} (99.6 µL, 0.199 mmol) in dioxane (474 µL) was purged with Ar _{( gas )} , sealed and heated at 110 °C Stir overnight. After cooling to room temperature, the reaction mixture was diluted with DCM and extracted with water. The organic extracts were dried over anhydrous Na ₂ SO _{4 ( solid )} , filtered and concentrated in vacuo. The crude residue was purified by silica chromatography (0-3% MeOH/DCM) to afford the title compound (16.0 mg, 57% yield). MS (apci) m/z = 297.2 (M+H).

example 6

7-( tertiary butyl )-5-(3- Cyclopropyl -1-( Tetrahydro -2H- pyran -2- base )-1H- pyrazole -5- base )-7H- pyrrolo [2,3-d] pyrimidine -4- amine

In a pressure vessel, with 2 M K2CO3 (aq) (712 µL, 1.4 mmol), 3-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5 ,5-Tetramethyl-1,3,2-dioxaborol-2-yl)-1H-pyrazole (83 mg, 0.26 mmol) and Pd(PPh3)4 (6.9 mg, 0.0059 mmol) treated 7- Solution of (tert-butyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Intermediate P3; 75 mg, 0.24 mmol) in dioxane (949 µL). The resulting mixture was bubbled with Ar(g) for 5 min, sealed and stirred at 100 °C for 3 days. After cooling to room temperature, the reaction mixture was diluted with DCM and extracted with water in PS Frit. The organic extracts were concentrated in vacuo and the crude residue was purified by silica chromatography (0-100% EtOAc/hexanes) to afford the title compound (12 mg, 13% yield). MS (apci) m/z = 381.2 (M+H).

example 7

7-( tertiary butyl )-5-(1H-1,2,3- Triazole -4- base )-7H- pyrrolo [2,3-d] pyrimidine -4- amine

Step 1: Preparation of 7-( tert-butyl )-5-(( trimethylsilyl ) ethynyl )-7H- pyrrolo [2,3-d] pyrimidin -4- amine . In a pressure vessel, 7-(tert-butyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine ( Intermediate P3 ; 500 mg, 1.58 mmol), CuI (75.3 mg , 0.395 mmol) and PdCl ₂ ( PPh ₃ ) ₂ (111 mg, 0.158 mmol) in DMF (2.4 mL) and TEA (222 µL, 1.58 mmol) were bubbled with Ar _{( gas )} and ethynyl trimethyl Silane (329 µL, 2.37 mmol), then sealed and stirred overnight at room temperature. The reaction mixture was directly purified by silica chromatography (100% DCM) to afford the title compound (340 mg, 75% yield). MS (apci) m/z = 287.2 (M+H).

Step 2: Preparation of 7-( tert-butyl )-5- ethynyl -7H- pyrrolo [2,3-d] pyrimidin -4- amine . At 0°C, to 7-(tert-butyl)-5-((trimethylsilyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (194 mg, 0.677 mmol) in THF (4.52 mL) was added TBAF (1.02 mL, 2.03 mmol). After stirring in ice-water bath for 2 hours, the reaction mixture was quenched with water and extracted with EtOAc. The organic extracts were concentrated in vacuo and the residue was purified by silica chromatography (0-3% MeOH/DCM) to afford the title compound (121 mg, 83% yield). MS (apci) m/z = 215.1 (M+H).

Step 3: Preparation of 7-( tert-butyl )-5-(1H-1,2,3- triazol -4- yl )-7H- pyrrolo [2,3-d] pyrimidin -4 - amine . To 7-(tert-butyl)-5-ethynyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (121 mg, 0.56 mmol) in dioxane (5.6 mL) cooled to 0°C ) was added azidotrimethylsilane (127 µL, 0.960 mmol) and CuI (4.30 mg, 0.0226 mmol). The resulting mixture was stirred overnight at 100 °C. After cooling to room temperature, the reaction mixture was quenched with water and extracted with EtOAc. The organic extracts were concentrated and purified by silica chromatography (0-2% MeOH/DCM) to afford the title compound (50.8 mg, 35% yield). MS (apci) m/z = 258.2 (M+H).

example 8

7-( tertiary butyl )-5-(1- Ethyl -1H-1,2,3- Triazole -4- base )-7H- pyrrolo [2,3-d] pyrimidine -4- amine

7-(tert-butyl)-5-(1H-1,2,3-triazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine was stirred at room temperature ( Example 7 : A mixture of 24 mg, 0.0933 mmol), bromoethane (6.96 µL, 0.0933 mmol) and _{K2CO3 ( solid )} (6.45 mg, 0.0466 mmol) in _DMF (1.0 mL) overnight. The reaction mixture was diluted with water and extracted with DCM. After phase separation, the organic extracts were concentrated in vacuo and purified by silica chromatography (0-2% MeOH/DCM) to afford the title compound (4.2 mg, 16% yield). MS (apci) m/z = 286.1 (M+H).

example 9

7-(2- Cyclopropylpropane -2- base )-5-(1- Ethyl -1H-1,2,3- Triazole -4- base )-7H- pyrrolo [2,3-d] pyrimidine -4- amine

A mixture of bromoethane (62.1 µL, 0.832 mmol) and sodium azide (54.1 mg, 0.832 mmol) in 1:1 t-BuOH: _H2O (332 µL) was stirred at 80°C for 2 hours. After cooling to room temperature, 7-( ₂ -cyclopropylpropan-2-yl)-5- Ethynyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine ( Intermediate P4 ; 20 mg, 0.083 mmol) was treated the reaction mixture. The resulting mixture was stirred at 80°C for 2.5 hours, cooled to room temperature; then CuI (1.59 mg, 0.00832 mmol) and 7-(2-cyclopropylprop-2-yl)-5-ethynyl-7H-pyrrole were introduced and[2,3-d]pyrimidin-4-amine (20 mg, 0.083 mmol) in 1:1 t-BuOH:H ₂ O (332 µL). The resulting mixture was stirred at 80 °C for 48 hours, cooled to room temperature and partitioned between DCM and water. After phase separation, the organic extracts were washed with brine, dried over anhydrous Na ₂ SO _{4 ( solid )} , filtered and concentrated in vacuo. The crude residue was purified by silica chromatography (10% MeOH/DCM) to afford the title compound (3.4 mg, 13% yield). MS (apci) m/z = 312.2 (M+H).

example 10

5-(1- Cyclopropyl -1H-1,2,3- Triazole -4- base )-7-(2- Cyclopropylpropane -2- base )-7H- pyrrolo [2,3-d] pyrimidine -4- amine

Bromoethyl was replaced by bromocyclopropane using the same method as for 7-(2-cyclopropylpropan-2-yl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl )-7H-pyrrolo[2,3-d]pyrimidin-4-amine ( Example 9 ) to prepare the title compound (0.5 mg, 2% yield) in a similar procedure. In addition, it was necessary to extend the reaction duration to a total of 144 hours, increasing the reaction temperature to 90°C for the final 96 hours, and using additional bromocyclopropane (65.3 µL, 0.83 mmol) with 1:1 t-BuOH after the initial 72 hours. : H ₂ O (333 μL) replenished the reactants and changed the eluent of the silica chromatography (15% MeOH/DCM with 1.5% NH ₄ OH). MS (apci) m/z = 324.3 (M+H).

example 11

5-(3- Cyclopropyl -1-( Tetrahydro -2H- pyran -2- base )-1H- pyrazole -5- base )-7- Isopropyl -7H- pyrrolo [2,3-d] pyrimidine -4- amine

Step 1: Preparation of 4- chloro -5- iodo -7- isopropyl -7H- pyrrolo [2,3-d] pyrimidine . 4-Chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (2.8 g, 10.0 mmol), 2-bromopropane (1.1 mL, 12.0 mmol) and Cs ₂ CO _{3 ( Solid )} (3.92 g, 12.0 mmol) in DMF (20.0 mL) for 60 h, cooled to room temperature and diluted with EtOAc (50 mL). Washed with water (2 x 50 mL), then dried over anhydrous _{Na2SO4 ( solid )} , _filtered and concentrated in vacuo. The crude material was purified by silica chromatography (0-30% EtOAc/hexanes) to afford the title compound (2.64 g, 82% yield). MS (apci) m/z = 322.0 (M+H).

Step 2: Preparation of N-(2,4- dimethoxybenzyl )-5- iodo -7- isopropyl -7H- pyrrolo [2,3-d] pyrimidin -4- amine . 4-Chloro-5-iodo-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine (215 mg, 0.669 mmol) and (2,4-dimethoxyphenyl ) a mixture of methylamine (301 µL, 2.0 mmol) in DMSO (3.3 mL) overnight. After cooling to room temperature, the reaction mixture was diluted with EtOAc and washed successively with water and brine. The organic layer was dried over anhydrous Na ₂ SO _{4 ( solid )} , filtered and concentrated in vacuo to give the title compound (302 mg, quantitative yield). MS (apci) m/z = 453.0 (M+H).

Step 3: Preparation of 5- iodo -7- isopropyl -7H- pyrrolo [2,3-d] pyrimidin -4- amine . Stir N-(2,4-dimethoxybenzyl)-5-iodo-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (302 mg , 0.67 mmol) and _Et3SiH (160.0 μL, 1.0 mmol) in TFA (3.3 mL) for 4 h, then concentrated, diluted with _DCM and washed sequentially with saturated _{Na2CO3 ( aq )} and brine. The organic layer was dried over anhydrous Na ₂ SO _{4 ( solid )} , filtered and concentrated in vacuo. The crude material was purified by silica chromatography (1-10% MeOH/DCM) to afford the title compound (188.6 mg, 93% yield). MS (apci) m/z = 303 (M+H).

Step 4: Preparation of 5-(3- cyclopropyl -1-( tetrahydro -2H- pyran -2- yl )-1H- pyrazol -5- yl )-7- isopropyl -7H- pyrrolo [ 2,3-d] pyrimidin -4- amine . In a pressure vessel, a solution of 5-iodo-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (189 mg, 0.62 mmol) in dioxane (2.5 mL) was used 2 MK ₂ CO _{3 ( aq )} (1.9 mL, 3.8 mmol), 3-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetra Methyl-1,3,2-dioxaborol-2-yl)-1H-pyrazole (219 mg, 0.69 mmol) and Pd(PPh ₃ ) ₄ (18 mg, 0.016 mmol) were treated with Ar _{( gas )} was bubbled for 5 minutes. The reaction was sealed and stirred overnight at 100 °C. After cooling to room temperature, direct purification by silica chromatography (0-100% EtOAc/hexanes) followed by trituration with MTBE gave the title compound (6.8 mg, 3% yield). MS (apci) m/z = 367.2 (M+H).

example 12

2,2,2- Trifluoroacetate 5-(5- Cyclopropyl iso Oxazole -3- base )-7H- pyrrolo [2,3-d] pyrimidine -4- amine

In a sealed tube, stir 5-(5-cyclopropylisoxazol-3-yl)-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine- A mixture of 4-amine ( Example 3 , _{Step 1; 50 mg, 0.13 mmol) and K2CO3(aq ) ( 54 mg} , 0.39 mmol) in MeOH (2.60 mL) for 30 min. After cooling to room temperature, the reaction mixture was concentrated in vacuo. The resulting residue was purified by reverse phase chromatography (0-95% ACN/water with 0.1% TFA) to afford the title compound (27 mg, 86% yield). MS (apci) m/z = 242.2 (M+H).

example 13

2,2,2- Trifluoroacetate 4- Amino -5-(5- Cyclopropylisoxazole -3- base )-7- Isopropyl -7H- pyrrolo [2,3-d] pyrimidine -6- formaldehyde

Step 1: Preparation of 4- chloro -7- isopropyl -7H- pyrrolo [2,3-d] pyrimidine -5- carbaldehyde . A solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde ( intermediate P1 , step 1; 3.6 g, 19.8 mmol) in DMF (40 mL) was washed with Cs ₂ CO ₃ (7.1 g, 21.8 mmol) and 2-bromopropane (2.2 mL, 23.8 mmol), followed by stirring overnight at 50°C. After cooling to room temperature, the reaction was diluted with water (100 mL), filtered, rinsed with water (30 mL) and then air dried to give the title compound (3.1 g, 70%) as an off-white solid. MS (apci) m/z = 224.1 (M+H).

Step 2: Preparation of 4- chloro -7- isopropyl -7H- pyrrolo [2,3-d] pyrimidine -5- carbaldehyde oxime . 4-Chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde (1.15 g, 5.14 mmol), NH ₂ OH-HCl (0.39 g, 5.66 mmol) were stirred at 50 °C ) and NaOAc (0.46 g, 5.66 mmol) in EtOH (26 mL) for 30 min. After cooling to room temperature, the reaction was diluted with DCM (50 mL) and filtered through a pad of Celite®, and the filtrate was concentrated to give the title compound (1.25 g, quantitative) as a pale yellow solid. MS (apci) m/z = 239.1 (M+H).

Step 3: Preparation of 3-(4- chloro -7- isopropyl -7H- pyrrolo [2,3-d] pyrimidin -5- yl )-5- cyclopropylisoxazole . Add 4-chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde oxime (0.47 g, 1.97 mmol) and KHCO ₃ (0.39 g, 3.94 mmol) in DMF (10 mL ) were added successively to the mixture in cyclopropylacetylene (0.5 mL, 5.91 mmol) and NCS (0.289 g, 2.17 mmol). The reaction was stirred overnight at 35 °C, then cooled to room temperature, diluted with EtOAc and washed with water. The organic layer was dried ( _Na2SO4 ), filtered, concentrated and purified by silica chromatography (0-50% EtOAc/hexanes ₎ to give the title compound (285 mg, 48%) as a light yellow solid. MS (apci) m/z = 303.1 (M+H).

Step 4: Preparation of 4- chloro -5-(5- cyclopropylisoxazol -3- yl )-7- isopropyl- 7H- pyrrolo [2,3-d] pyrimidine -6- carbaldehyde . To 3-(4-chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-5-cyclopropylisoxazole (61 mg, 0.20 mmol) in THF (2.0 mL) was added LDA (2 M, THF) (0.2 mL, 0.40 mmol). After stirring for 30 minutes, ethyl formate (49 µL, 0.60 mmol) was introduced and the reaction mixture was allowed to warm to room temperature. Then, the reaction mixture was quenched with NH ₄ Cl (sat.) and extracted with EtOAc. The combined organic extracts were dried ( _Na2SO4 ), filtered, concentrated and purified by silica chromatography (0-50% EtOAc/hexanes) to give the title compound (15 mg, 23%) as _a white solid . MS (apci) m/z = 331.1 (M+H).

Step 5: Preparation of 2,2,2- trifluoroacetic acid 4- amino -5-(5- cyclopropylisoxazol- 3- yl )-7- isopropyl -7H- pyrrolo [2,3- d] pyrimidine -6- carbaldehyde . In a sealed pressure vessel, heat 4-chloro-5-(5-cyclopropylisoxazol-3-yl)-7-isopropyl-7H-pyrrolo[2,3-d] at 80°C Pyrimidine-6-carbaldehyde (9 mg, 0.03) in _NH3 (2 M, IPA) (1 mL, 2 mmol) for 4 hours. After cooling to room temperature, the mixture was concentrated and purified by reverse phase chromatography (0-95% MeCN/water with 0.1% TFA) to afford the title product (6 mg, 52%) as a white solid. MS (apci) m/z = 312.2 (M+H).

example 14

(4- Amino -5-(5- Cyclopropylisoxazole -3- base )-7- Isopropyl -7H- pyrrolo [2,3-d] pyrimidine -6- base ) Methanol

At 0°C, to 2,2,2-trifluoroacetic acid 4-amino-5-(5-cyclopropylisoxazol-3-yl)-7-isopropyl-7H-pyrrolo[2, 3-d] To a solution of pyrimidine-6-carbaldehyde ( Example 13 , 0.66 g, 1.6 mmol) in MeOH (7.8 mL) was added _NaBH4 (0.059 g, 1.6 mmol). After stirring for 5 minutes, the reaction was quenched with water and then extracted with EtOAc. The combined organic extracts were dried ( _Na2SO4 ), filtered, _concentrated and purified by silica chromatography (0-50% EtOAc/hexanes) to give the title product (420 mg, 86%). MS (apci) m/z = 314.2 (M+H).

example 15

2,2,2- Trifluoroacetate 3-(4- Amino -7- Isopropyl -7H- pyrrolo [2,3-d] pyrimidine -5- base )-5- Cyclopropylisoxazole -4- Formamide

Step 1: Preparation of ethyl 3- cyclopropylpropionate . A solution of ethynylcyclopropane (0.78 g, 11.8 mmol) in THF (8 mL) was bubbled with argon and cooled to -78 °C, then n-BuLi (2.5 M, THF) (5.2 mL, 13.0 mmol). The mixture was stirred at -78°C for 30 minutes and at -10°C for 45 minutes. The reaction mixture was then cooled to -78 °C, followed by the dropwise addition of ethyl chloroformate (1.24 mL, 13.0 mmol). The reaction mixture was allowed to warm to room temperature and stirred overnight, then partitioned between EtOAc and saturated _NH4Cl (aq). After phase separation, the organic layer was washed with water and then dried (Na ₂ SO ₄ ), filtered and concentrated to give the title compound (1.6 g, 98%). MS (apci) m/z = 139.1 (M+H).

Step 2: Preparation of ethyl 3-(4- chloro -7- isopropyl - 7H - pyrrolo [2,3-d] pyrimidin -5- yl )-5- cyclopropylisoxazole -4- carboxylate . In a pressure vessel, 4-chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde oxime ( Example 13 , Step 2; 96.6 mg, 0.40 mmol) was dissolved in 1,2- A solution in dimethoxyethane (8.1 mL) was treated with NCS (59.4 mg, 0.44 mmol), then sealed and stirred at room temperature overnight. Ethyl 3-cyclopropylpropanoate (559 µL, 4.05 mmol) and _KHCO3 (122 mg, 1.21 mmol) were introduced, and the reaction was resealed and heated at 65 °C for 2 hours. The reaction mixture was filtered, concentrated and purified by silica chromatography (0-70% EtOAc/hexanes) to afford the title compound (82.4 mg, 54%). MS (apci) m/z = 375.1 (M+H).

Step 3: Preparation of 5- cyclopropyl -3-(4-((2,4 -dimethoxybenzyl ) amino )-7- isopropyl- 7H- pyrrolo [2,3-d] pyrimidin -5- yl ) isoxazole -4- carboxylic acid ethyl ester . 3-(4-Chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-5-cyclopropylisoxazole-4-carboxylic acid ethyl ester (82.4 mg, 0.22 mmol) in DMSO (2.5 mL) was treated with (2,4-dimethoxyphenyl)methanamine (0.1 mL, 0.66 mmol) and stirred at 85 °C for 1 h. After cooling to room temperature, the reaction mixture was diluted with _H2O and extracted with DCM. The combined organic layers were passed through a phase separator frit, concentrated and purified by silica chromatography (0-70% EtOAc/hexanes) to afford the title compound (85.5 mg, 77%). MS (apci) m/z = 506.2 (M+H).

Step 4: Preparation of 5- cyclopropyl -3-(4-((2,4 -dimethoxybenzyl ) amino )-7- isopropyl- 7H- pyrrolo [2,3-d] pyrimidin -5- yl ) isoxazole -4- carboxylate hydrochloride . Stir 5-cyclopropyl-3-(4-((2,4-dimethoxybenzyl)amino)-7-isopropyl-7H-pyrrolo[2,3-d at room temperature ]pyrimidin-5-yl)isoxazole-4-carboxylic acid ethyl ester (85.5 mg, 0.17 mmol) and lithium hydroxide hydrate (28.4 mg, 0.68 mmol) in THF:MeOH:H ₂ O in a 1:1:1 mixture (1.2 mL) for 1 h and then heated at reflux for 1 h. The reaction mixture was concentrated, dissolved in HCl (1 M, aq) and extracted with EtOAc. The combined organic extracts were dried ( _Na2SO4 ), filtered and _concentrated to give the title compound (66 mg, 76%) as a white solid. MS (apci) m/z = 478.2 (M+H).

Step 5: Preparation of 5- cyclopropyl -3-(4-((2,4 -dimethoxybenzyl ) amino )-7- isopropyl- 7H- pyrrolo [2,3-d] pyrimidin -5- yl ) isoxazole -4- carboxamide . 5-cyclopropyl-3-(4-((2,4-dimethoxybenzyl)amino)-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5- base) isoxazole-4-carboxylate hydrochloride (12.9 mg, 0.025 mmol) and ammonium chloride (6.7 mg, 0.12 mmol) in DCM (0.5 mL) with DIEA (66 µL, 0.38 mmol) and HATU (19.1 mg, 0.050 mmol) was treated followed by stirring at room temperature for 30 minutes. The reaction mixture was filtered and purified by silica chromatography (0-15% MeOH/DCM with 1.5% _NH4OH ) to afford the title compound (15.8 mg, quantitative). MS (apci) m/z = 477.2 (M+H).

Step 6 : Preparation of 3-(4- amino -7- isopropyl - 7H- pyrrolo [2,3-d] pyrimidin -5- yl )-5- cyclopropyl from 2,2,2-trifluoroacetic acid Isoxazole -4- carboxamide . 5-cyclopropyl-3-(4-((2,4-dimethoxybenzyl)amino)-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5- A solution of isoxazole-4-carboxamide (12 mg, 0.025 mmol) in DCM (0.25 mL) was treated with TFA (97.0 µL, 1.26 mmol) and stirred for 30 min. The reaction mixture was concentrated, dissolved in DCM and concentrated again to give the title product (17.9 mg, quant) as a white solid. MS (apci) m/z = 327.2 (M+H).

example 16

2,2,2- Trifluoroacetate 3-(4- Amino -7- Isopropyl -7H- pyrrolo [2,3-d] pyrimidine -5- base )-5- Cyclopropyl -N- Methylisoxazole -4- Formamide

Ammonium chloride in step 5 was replaced with methylamine hydrochloride using the same method as for 2,2,2-trifluoroacetic acid 3-(4-amino-7-isopropyl-7H-pyrrolo[2,3 -d] Pyrimidin-5-yl)-5-cyclopropylisoxazole-4-carboxamide The title product (19.6 mg, quantitative yield) was prepared by a similar procedure as described ( Example 15 ). MS (apci) m/z = 341.2 (M+H).

example 17

7- Cyclopentyl -5-(5- Cyclopropylisoxazole -3- base )-7H- pyrrolo [2,3-d] pyrimidine -4- amine

Step 1: Preparation of 3-(4- chloro -7- cyclopentyl - 7H- pyrrolo [2,3-d] pyrimidin -5- yl )-5- cyclopropylisoxazole . To 3-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-5-cyclopropylisoxazole ( intermediate P18 ) (766 mg, 2.94 mmol) at room temperature ), cyclopentanol (320 µL, 3.53 mmol) and triphenylphosphine (925 mg, 3.53 mmol) in THF (15 mL) was added dropwise with DIAD (112 µL, 0.58 mmol) and stirred for 30 min. The reaction was then concentrated and purified by silica chromatography (0-40% EtOAc/hexanes) to afford the title compound (0.92 g, 95%) as a light yellow oil. MS (apci) m/z = 329.1 (M+H).

Step 2: Preparation of 7- cyclopentyl -5-(5- cyclopropylisoxazol- 3- yl )-7H- pyrrolo [2,3-d] pyrimidin -4- amine . 3-(4-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-5-cyclopropylisoxazole (33 mg, 0.10 mmol), concentrated NH ₄ OH (0.5 mL) and 1,4-dioxane (0.5 mL) were sealed in a pressure vessel and heated at 100 °C for 4 hours. After cooling to room temperature, the reaction was concentrated to dryness, then triturated with water and filtered. The resulting solid was purified by reverse phase chromatography (0-95% MeCN/water with 0.1% TFA). The combined product fractions were concentrated to about 5 mL, then neutralized with saturated _NaHCO3 (aq). The resulting suspension was filtered, rinsed with water and dried to give the title product (28 mg, 90%) as a white solid. MS (apci) m/z = 310.3 (M+H).

Substituting the appropriate commercially available alcohol for the cyclopentanol in Step 1, the compounds in the table below were prepared in a similar manner as described in Example 17 .

example 20

7- Cyclopropyl -5-(5- Cyclopropylisoxazole -3- base )-7H- pyrrolo [2,3-d] pyrimidine -4- amine

酸(51 mg，0.60 mmol)、2,2'-聯吡啶(47 mg，0.30 mmol)、Cu(OAc)₂ (54 mg，0.30 mmol)及Na₂ CO₃ (63 mg，0.60 mmol)於1,2-二氯乙烷(3 mL)中之混合物密封於壓力容器中且在80℃下攪拌4小時。在冷卻至室溫之後，反應物用EtOAc (20 mL)稀釋且經由短矽藻土墊過濾。濃縮濾液，得到粗3-(4-氯-7-環丙基-7H-吡咯并[2,3-d]嘧啶-5-基)-5-環丙基異噁唑中間物，使其溶解於1:1濃NH₄ OH/1,4-二噁烷(3 mL)中，接著密封於壓力容器中且在100℃下加熱3小時。在冷卻至室溫之後，濃縮混合物且藉由逆相層析(具有0.1% TFA之0-95% MeCN/水)純化。濃縮合併之產物溶離份，用NaHCO₃ (飽和)稀釋且用DCM萃取。乾燥(Na₂ SO₄ )合併之有機萃取物，過濾且濃縮，得到呈白色固體之標題產物(8 mg，10%)。MS (apci) m/z = 282.2 (M+H)。3-(4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-5-cyclopropylisoxazole ( intermediate P18 ) (78 mg, 0.30 mmol), cyclopropyl

acid (51 mg, 0.60 mmol), 2,2'-bipyridine (47 mg, 0.30 mmol), Cu(OAc) ₂ (54 mg, 0.30 mmol) and Na ₂ CO ₃ (63 mg, 0.60 mmol) in 1 , the mixture in 2-dichloroethane (3 mL) was sealed in a pressure vessel and stirred at 80 °C for 4 h. After cooling to room temperature, the reaction was diluted with EtOAc (20 mL) and filtered through a short pad of Celite. The filtrate was concentrated to give the crude 3-(4-chloro-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-5-cyclopropylisoxazole intermediate which was dissolved in 1:1 concentrated _NH4OH /1,4-dioxane (3 mL), then sealed in a pressure vessel and heated at 100 °C for 3 hours. After cooling to room temperature, the mixture was concentrated and purified by reverse phase chromatography (0-95% MeCN/water with 0.1% TFA). The combined product fractions were concentrated, diluted with _NaHCO3 (sat) and extracted with DCM. The combined organic extracts were dried ( _Na2SO4 ), filtered and concentrated to give the title product (8 mg, 10%) as _a white solid. MS (apci) m/z = 282.2 (M+H).

example twenty one

5-(5- Cyclopropylisoxazol -3- yl ) -7- phenyl -7H- pyrrolo [2,3-d] pyrimidin -4- amine

酸置換環丙基

，以與如實例 20 中所描述類似之方式製備標題產物。MS (apci) m/z = 318.1 (M+H)。With phenyl

Acid Replacement Cyclopropyl

, the title product was prepared in a similar manner as described in Example 20 . MS (apci) m/z = 318.1 (M+H).

example twenty two

7- Benzyl -5-(5- Cyclopropylisoxazole -3- base )-7H- pyrrolo [2,3-d] pyrimidine -4- amine

5-(5-Cyclopropylisoxazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine ( Intermediate P20 ) (36 mg, 0.15 mmol) was stirred at room temperature , (bromomethyl)benzene (31 mg, 0.18 mmol) and Cs ₂ CO ₃ (58 mg, 0.18 mmol) in DMF (746 µL) for 1 h. Purified directly by reverse phase chromatography (0-95% MeCN/water with 0.1% TFA). The combined product fractions were concentrated, diluted with _NaHCO3 (sat) and extracted with DCM. The combined organic extracts were dried ( _Na2SO4 ), filtered and _concentrated to give the title product (23 mg, 47%) as a white solid. MS (apci) m/z = 332.1 (M+H).

藉由用SFC (ChiralTech OJ-H/4.6 mm×250 mm；4 mL/min；MeOH:IPA:DEA (80:20:0.1)/CO₂ )進行(3-(4-胺基-5-(5-環丙基異噁唑-3-基)-7H-吡咯并[2,3-d]嘧啶-7-基)環丁基)甲醇(實例 28 )(10 mg，0.031 mmol)之對掌性分離來製備標題產物。主要異構體首先溶離管柱，且隨後經由NOE NMR研究測定為((1s,3s)-3-(4-胺基-5-(5-環丙基異噁唑-3-基)-7H-吡咯并[2,3-d]嘧啶-7-基)環丁基)甲醇(5.6 mg，56%)。次要異構體隨後溶離且指定為反式產物((1r,3r)-3-(4-胺基-5-(5-環丙基異噁唑-3-基)-7H-吡咯并[2,3-d]嘧啶-7-基)環丁基)甲醇(1.8 mg，18%)。MS (apci) m/z = 326.2 (M+H)。The compounds in the table below were prepared in a similar manner as described in Example 22 , using a commercially available electrophile charge as mentioned herein to displace (bromomethyl)benzene.

(3-(4-Amino- _5- ( 5-cyclopropylisoxazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclobutyl)methanol ( Example 28 ) (10 mg, 0.031 mmol) isolated to prepare the title product. The major isomer eluted first from the column and was subsequently determined by NOE NMR studies as ((1s,3s)-3-(4-amino-5-(5-cyclopropylisoxazol-3-yl)-7H -pyrrolo[2,3-d]pyrimidin-7-yl)cyclobutyl)methanol (5.6 mg, 56%). The minor isomer was subsequently eluted and assigned to the trans product ((1r,3r)-3-(4-amino-5-(5-cyclopropylisoxazol-3-yl)-7H-pyrrolo[ 2,3-d]pyrimidin-7-yl)cyclobutyl)methanol (1.8 mg, 18%). MS (apci) m/z = 326.2 (M+H).

example 30

1-(3-(4- Amino -7- Isopropyl -7H- pyrrolo [2,3-d] pyrimidine -5- base )-5- Cyclopropylisoxazole -4- base ) ethane -1,2- diol

Step 1: Preparation of 3-(4- chloro -7- isopropyl -7H- pyrrolo [2,3-d] pyrimidin -5- yl )-5- cyclopropylisoxazole -4- carbaldehyde . At room temperature, to (3-(4-chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-5-cyclopropylisoxazol-4-yl ) to a solution of methanol ( Intermediate P19 ) (1.0 g, 3.0 mmol) in DCM (15 mL) was added Dess-Martin periodinane (1.53 g, 3.6 mmol) and stirred for 1 h. Washed with sat. _{NaHCO3 (} 3x) and water (1x), then dried ( _Na2SO4 ), filtered and concentrated. The crude material was purified by silica chromatography (0-100% MTBE/hexanes) to afford the title compound (963 mg, 97%). MS (apci) m/z = 331.1 (M+H).

Step 2: Preparation of 3-(4- chloro -7- isopropyl -7H- pyrrolo [2,3-d] pyrimidin -5- yl )-5- cyclopropyl -4- vinylisoxazole . To a solution of methyltriphenylphosphonium bromide (77.4 mg, 0.22 mmol) in THF (9 mL) was added 1 M ^KOBut (aq) (0.22 mL, 0.22 mmol) at 0 °C and stirred for 15 min (Solution A). In a separate flask, make 3-(4-chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-5-cyclopropylisoxazole-4-carbaldehyde (717 mg, 2.2 mmol) in THF (9 mL) was cooled to -78 °C (Solution B). Then, solution A was added dropwise to solution B at -78°C and stirred for 30 minutes. The reaction was concentrated and purified by silica chromatography (0-100% MTBE/hexanes) to afford the title compound (621 mg, 87%) as a white solid. MS (apci) m/z = 329.1 (M+H).

Step 3: Preparation of 5-(5- cyclopropyl -4- vinylisoxazol -3- yl )-7- isopropyl- 7H- pyrrolo [2,3-d] pyrimidin -4- amine . 3-(4-Chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-5-cyclopropyl-4-vinylisoxazole (100 mg, 0.30 mmol) in 1:1 dioxane:cone _NH4OH (6 mL) was sealed in a pressure vessel and stirred at 80 °C for 15 h. After cooling to room temperature, the reaction mixture was concentrated, then dissolved in H ₂ O (10 mL) and extracted with DCM (2×10 mL). The combined organic extracts were dried ( _MgSO4 ), filtered and concentrated to give the title compound (66.6 mg, 71%) as a white solid. MS (apci) m/z = 310.2 (M+H).

Step 4: Preparation of 1-(3-(4- amino -7- isopropyl -7H- pyrrolo [2,3-d] pyrimidin -5- yl )-5- cyclopropylisoxazole -4- base ) ethane -1,2- diol . To 5-(5-cyclopropyl-4-vinylisoxazol-3-yl)-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine cooled to 0°C (66.6 mg, 0.215 mmol) in THF (1.1 mL) and water (0.4 mL) were added successively 4-oxidized 4-methylmorpholine (50.4 mg, 0.43 mmol) and OsO ₄ (4% aqueous solution) ( 169 µL, 0.0215 mmol). The reaction was allowed to warm to room temperature and stirred for 2 days. It was then diluted with saturated _Na2S2O3 (aq) (10 mL) and extracted _with DCM (3 _x 10 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated to give the title product (67 mg, 91%) as a beige solid. MS (apci) m/z = 344.1 (M+H).

example 31

5-(5- Cyclopropyl -4-( pyridine -2- base ) Isoxazole -3- base )-7- Isopropyl -6- methyl -7H- pyrrolo [2,3-d] pyrimidine -4- amine

Step 1: Preparation of 3-(4- chloro -7- isopropyl - 6- methyl -7H- pyrrolo [2,3-d] pyrimidin -5- yl )-5- cyclopropyl -4- iodoiso Oxazole . To 3-(4-chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-5-cyclopropylisoxazole ( Example 13 , Step 3) To a solution of (604 mg, 1.99 mmol) in THF (10 mL) was added sequentially DIEA (114 µL, 0.80 mmol) and nBuLi (2.5 M, THF) (1.1 mL, 2.79 mmol). After stirring for 20 minutes, _CH3I (249 µL, 3.99 mmol) was introduced. The resulting solution was stirred at -78°C for 30 minutes, then allowed to warm to room temperature. The reaction was quenched with _NH4Cl (sat) and extracted with EtOAc. The combined organic extracts were dried ( _Na2SO4 ), filtered and concentrated to give crude _3- (4-chloro-7-isopropyl-6-methyl-7H-pyrrolo[2,3-d]pyrimidine- 5-yl)-5-cyclopropylisoxazole intermediate, which was dissolved in MeCN (10 mL), followed by treatment with NIS (673 mg, 2.99 mmol) and TFA (461 µL, 5.98 mmol). The resulting mixture was stirred at room temperature for 2 h, then quenched with 10% Na ₂ S ₂ O ₃ (5 mL) and saturated NaHCO ₃ (20 mL), then extracted with EtOAc. The combined organic extracts were dried ( _Na2SO4 ), filtered, concentrated and purified by silica chromatography (0-50% EtOAc/hexanes ₎ to give the title compound (384 mg, 44%) as a white solid . MS (apci) m/z = 443.0 (M+H).

Step 2: Preparation of 5-(5- cyclopropyl -4- iodoisoxazol -3- yl )-7- isopropyl -6- methyl- 7H - pyrrolo [2,3-d] pyrimidine -4 - Amines . 3-(4-chloro-7-isopropyl-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-5-cyclopropyl-4-iodoisoxazole ( 82 mg, 0.19 mmol) in 1,4-dioxane (1.8 mL) and conc. NH ₄ OH (926 µL) was sealed in a pressure vessel and stirred at 80°C for 2 hours, then at 90-105°C Stirring was continued for a total of 3 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted with DCM. The combined organic extracts were dried ( _Na2SO4 ), filtered and concentrated to give the title compound (72 mg, 92%) as _a pale yellow solid. MS (apci) m/z = 424.1 (M+H).

Step 3: Preparation of 5-(5- cyclopropyl -4-( pyridin -2- yl ) isoxazol -3- yl )-7- isopropyl -6- methyl -7H- pyrrolo [2,3 -d] pyrimidin -4- amine . 5-(5-cyclopropyl-4-iodoisoxazol-3-yl)-7-isopropyl-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (36 mg, 0.085 mmol), a mixture of _PdCl2 ( _PPh3 ) ₂ (11.9 mg, 0.017 mmol) and 2-(tributylstannyl)pyridine (110 µL, 0.34 mmol) in toluene (0.85 mL) was flushed with _N2 , sealed in a pressure vessel, followed by stirring at 110° C. for 14 hours. After cooling to room temperature, the reaction mixture was concentrated and analyzed by reverse phase chromatography (first column eluent: 0-95% MeCN/water with 0.1% TFA, then second column eluent: with 0.1% conc. _NH4OH 0-95% MeCN/water) gave the title product (3 mg, 9%) as a white solid. MS (apci) m/z = 375.1 (M+H).

example 32

5-(5- Cyclopropylisoxazole -3- base )-7- Isopropyl -6- methyl -7H- pyrrolo [2,3-d] pyrimidine -4- amine

The title product from step 3 of Example 31 was isolated during chromatographic purification (first column eluent: 0-95% MeCN/water with 0.1% TFA). The combined fractions containing the title product were concentrated, diluted with saturated _NaHCO3 , and extracted with DCM. The combined organic extracts were concentrated, triturated with water, then filtered and dried to give the title product (8 mg, 32%) as a white solid. MS (apci) m/z = 298.2 (M+H).

example 33

5-(5- Cyclopropyl -4-(1- methyl -1H- imidazole -4- base ) Isoxazole -3- base )-7- Isopropyl -6- methyl -7H- pyrrolo [2,3-d] pyrimidine -4- amine

5-(5-cyclopropyl-4-iodoisoxazol-3-yl)-7-isopropyl-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine ( example Step 2 of 31 ) (36 mg, 0.085 mmol), PdCl ₂ (PPh ₃ ) ₂ (12 mg, 0.017 mmol) and 1-methyl-4-(tributylstannyl)-1H-imidazole (126 mg, 0.34 mmol) in toluene (851 µL) was flushed with _N2 , sealed in a pressure vessel and stirred at 110 °C for 14 h. After cooling to room temperature, the reaction mixture was concentrated and purified by reverse phase chromatography (0-95% MeCN/water with 0.1% TFA). The combined product fractions were concentrated to dryness, dissolved in MeOH and passed through a PL- _HCO3 MP SPE cartridge. The filtrate was concentrated to give the title product (8 mg, 25%) as a white solid. MS (apci) m/z = 378.2 (M+H).

example 34

2,2,2- Trifluoroacetate 6-( Aminomethyl )-7- Isopropyl -5-(3- methyl -1H- pyrazole -5- base )-7H- pyrrolo [2,3-d] pyrimidine -4- amine

6-(aminomethyl)-N-(2,4-dimethoxybenzyl)-7-isopropyl-5-(3-methyl-1H-pyrazole-5 -yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine ( intermediate P21 ) (35 mg, 0.080 mmol) in TFA (1.6 mL) for 2 hours, then concentrated and filtered by reverse Purification by phase chromatography (0-95% MeCN/water with 0.1% TFA) afforded the title product (5 mg, 22%) as a white solid. MS (apci) m/z = 286.3 (M+H).

Claims (10)

A compound of formula I or a pharmaceutically acceptable salt thereof,

where: ^R1 is

, wherein R ^a is cyclopropyl and R ^b is hydrogen, iodine,

,

,

,

or

; or R ¹ is

,

,

,

or

; R ² is hydrogen, C1-C6 alkyl, fluoro C1-C6 alkyl, cyano C1-C6 alkyl, hydroxyl C1-C6 alkyl, Ar ² , (Ar ² ) C1-C6 alkyl-, hetCyc ² , Cyc ³ or (Cyc ³ ) C1-C6 alkyl-; Ar ² is phenyl, which is unsubstituted or substituted by one or more substituents independently selected from the following: C1-C6 alkyl, fluoro C1- C6 alkyl, halogen and hydroxyl; Cyc ³ is unsubstituted or C3-C6 cycloalkyl substituted by hydroxyl C1-C6 alkyl-substituted; hetCyc ² is a 4-6 membered saturated heterocyclic ring with 1-2 independent A ring heteroatom selected from N and O; and ^Ry is hydrogen, HC(=O)-, hydroxy C1-C6 alkyl-, C1-C6 alkyl-, or amino C1-C6 alkyl-. Such as the compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein ^R is hydrogen, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, benzyl, Propylene oxide (oxetane),

,

,

,

,

or

. Such as the compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R ^y is hydrogen, methyl,

Such as the compound of claim 1 or a pharmaceutically acceptable salt thereof, which is selected from: 5-(5-cyclopropyl-4-iodoisoxazol-3-yl)-7-isopropyl-7H-pyrrole A[2,3-d]pyrimidin-4-amine; 5-(5-cyclopropyl-4-(pyridin-2-yl)isoxazol-3-yl)-7-isopropyl-7H-pyrrole A[2,3-d]pyrimidin-4-amine; 5-(5-cyclopropylisoxazol-3-yl)-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine- 4-amine; 7-(tert-butyl)-5-(5-cyclopropylisoxazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 7-( tert-butyl)-5-(1-cyclopropyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 7-(tert-butyl) -5-(3-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine; 7-(tert-butyl)-5-(1H-1,2,3-triazol-4-yl)-7H-pyrrolo[ 2,3-d]pyrimidin-4-amine; 7-(tertiary butyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)-7H-pyrrolo[ 2,3-d]pyrimidin-4-amine; 7-(2-cyclopropylprop-2-yl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl) -7H-pyrrolo[2,3-d]pyrimidin-4-amine; 5-(1-cyclopropyl-1H-1,2,3-triazol-4-yl)-7-(2-cyclopropyl Propan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 5-(3-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)- 1H-pyrazol-5-yl)-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 5-(5-cyclopropylisoxazol-3-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine; 4-amino-5-(5-cyclopropylisoxazol-3-yl)-7-isopropyl-7H-pyrrolo[ 2,3-d]pyrimidine-6-carbaldehyde; (4-amino-5-(5-cyclopropylisoxazol-3-yl)-7-isopropyl-7H-pyrrolo[2,3- d]pyrimidin-6-yl)methanol; 3-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-5-cyclopropylisoxazole -4-formamide; 3-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-5-cyclopropyl-N-methyliso Oxazole-4-carboxamide; 7-cyclopentyl-5-(5-cyclopropylisoxazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 7 -Cyclobutyl-5-(5-cyclopropylisoxazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 5-(5-cyclopropylisoxazole -3-yl)-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 7-cyclopropyl-5-(5-cyclopropylisoxazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 5-(5-cyclopropylisoxazol-3-yl) Azol-3-yl)-7-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 7-benzyl-5-(5-cyclopropylisoxazol-3-yl )-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 2-(4-amino-5-(5-cyclopropylisoxazol-3-yl)-7H-pyrrolo[2 ,3-d]pyrimidin-7-yl)propionitrile; 5-(5-cyclopropylisoxazol-3-yl)-7-(1,1,1-trifluoroprop-2-yl)-7H -pyrrolo[2,3-d]pyrimidin-4-amine; 1-(4-amino-5-(5-cyclopropylisoxazol-3-yl)-7H-pyrrolo[2,3- d] pyrimidin-7-yl)-2-methylpropan-2-ol; 5-(5-cyclopropylisoxazol-3-yl)-7-(oxetane-3-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine; (3-(4-amino-5-(5-cyclopropylisoxazol-3-yl)-7H-pyrrolo[2, 3-d]pyrimidin-7-yl)cyclobutyl)methanol; ((1s,3s)-3-(4-amino-5-(5-cyclopropylisoxazol-3-yl)-7H- Pyrrolo[2,3-d]pyrimidin-7-yl)cyclobutyl)methanol; ((1r,3r)-3-(4-amino-5-(5-cyclopropylisoxazole-3- yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclobutyl)methanol; 1-(3-(4-amino-7-isopropyl-7H-pyrrolo[2, 3-d]pyrimidin-5-yl)-5-cyclopropylisoxazol-4-yl)ethane-1,2-diol; 5-(5-cyclopropyl-4-(pyridine-2- base) isoxazol-3-yl)-7-isopropyl-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 5-(5-cyclopropylisoxazole -3-yl)-7-isopropyl-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 5-(5-cyclopropyl-4-(1-methyl-1H-imidazol-4-yl)isoxazol-3-yl)-7-isopropyl-6-methyl-7H-pyrrolo[ 2,3-d]pyrimidin-4-amine; and 6-(aminomethyl)-7-isopropyl-5-(3-methyl-1H-pyrazol-5-yl)-7H-pyrrolo [2,3-d]pyrimidin-4-amine; or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising a mixture of the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier. A use of the compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating RET-related cancer in a patient. The use according to claim 6, wherein the RET-related cancer is selected from the group consisting of lung cancer, papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, refractory differentiated thyroid cancer, type 2A or 2B Multiple endocrine neoplasia (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, gangliomatosis of gastrointestinal mucosa, and cervical cancer. The use according to claim 7, wherein the lung cancer is RET fusion lung cancer. The use according to claim 7, wherein the cancer is medullary thyroid cancer. The use according to claim 7, wherein the lung cancer is small cell lung cancer, non-small cell lung cancer, bronchiolopulmonary carcinoma or lung adenocarcinoma.